Modulators of ATP-binding cassette transporters

ABSTRACT

Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.

CROSS-REFERENCE

This application claims priority to U.S. Ser. Nos. 60/754,558, filed onDec. 28, 2005, and 60/802,580, filed on May 22, 2006, both of which arehereby incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to modulators of ATP-Binding Cassette(“ABC”) transporters or fragments thereof, including Cystic FibrosisTransmembrane Conductance Regulator (“CFTR”), compositions thereof andmethods therewith. The present invention also relates to methods oftreating ABC transporter mediated diseases using such modulators.

BACKGROUND OF THE INVENTION

ABC transporters are a family of membrane transporter proteins thatregulate the transport of a wide variety of pharmacological agents,potentially toxic drugs, and xenobiotics, as well as anions. ABCtransporters are homologous membrane proteins that bind and use cellularadenosine triphosphate (ATP) for their specific activities. Some ofthese transporters were discovered as multidrug resistance proteins(like the MDR1-P glycoprotein, or the multidrug resistance protein,MRP1), defending malignant cancer cells against chemotherapeutic agents.To date, 48 ABC Transporters have been identified and grouped into 7families based on their sequence identity and function.

ABC transporters regulate a variety of important physiological roleswithin the body and provide defense against harmful environmentalcompounds. Because of this, they represent important potential drugtargets for the treatment of diseases associated with defects in thetransporter, prevention of drug transport out of the target cell, andintervention in other diseases in which modulation of ABC transporteractivity may be beneficial.

One member of the ABC transporter family commonly associated withdisease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressedin a variety of cells types, including absorptive and secretoryepithelia cells, where it regulates anion flux across the membrane, aswell as the activity of other ion channels and proteins. In epitheliacells, normal functioning of CFTR is critical for the maintenance ofelectrolyte transport throughout the body, including respiratory anddigestive tissue. CFTR is composed of approximately 1480 amino acidsthat encode a protein made up of a tandem repeat of transmembranedomains, each containing six transmembrane helices and a nucleotidebinding domain. The two transmembrane domains are linked by a large,polar, regulatory (R)-domain with multiple phosphorylation sites thatregulate channel activity and cellular trafficking.

The gene encoding CFTR has been identified and sequenced (See Gregory,R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). Adefect in this gene causes mutations in CFTR resulting in CysticFibrosis (“CF”), the most common fatal genetic disease in humans. CysticFibrosis affects approximately one in every 2,500 infants in the UnitedStates. Within the general United States population, up to 10 millionpeople carry a single copy of the defective gene without apparent illeffects. In contrast, individuals with two copies of the CF associatedgene suffer from the debilitating and fatal effects of CF, includingchronic lung disease.

In patients with cystic fibrosis, mutations in CFTR endogenouslyexpressed in respiratory epithelia leads to reduced apical anionsecretion causing an imbalance in ion and fluid transport. The resultingdecrease in anion transport contributes to enhanced mucus accumulationin the lung and the accompanying microbial infections that ultimatelycause death in CF patients. In addition to respiratory disease, CFpatients typically suffer from gastrointestinal problems and pancreaticinsufficiency that, if left untreated, results in death. In addition,the majority of males with cystic fibrosis are infertile and fertilityis decreased among females with cystic fibrosis. In contrast to thesevere effects of two copies of the CF associated gene, individuals witha single copy of the CF associated gene exhibit increased resistance tocholera and to dehydration resulting from diarrhea—perhaps explainingthe relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed avariety of disease causing mutations (Cutting, G. R. et al. (1990)Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem,B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc.Natl. Acad. Sci. USA 87:8447-8451). To date, >1000 disease causingmutations in the CF gene have been identified(http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation isa deletion of phenylalanine at position 508 of the CFTR amino acidsequence, and is commonly referred to as ΔF508-CFTR. This mutationoccurs in approximately 70% of the cases of cystic fibrosis and isassociated with a severe disease.

The deletion of residue 508 in ΔF508-CFTR prevents the nascent proteinfrom folding correctly. This results in the inability of the mutantprotein to exit the ER, and traffic to the plasma membrane. As a result,the number of channels present in the membrane is far less than observedin cells expressing wild-type CFTR. In addition to impaired trafficking,the mutation results in defective channel gating. Together, the reducednumber of channels in the membrane and the defective gating lead toreduced anion transport across epithelia leading to defective ion andfluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studieshave shown, however, that the reduced numbers of ΔF508-CFTR in themembrane are functional, albeit less than wild-type CFTR. (Dalemans etal. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk andFoskett (1995), J. Cell. Biochem. 270: 12347-50). In addition toΔF508-CFTR, other disease causing mutations in CFTR that result indefective trafficking, synthesis, and/or channel gating could be up- ordown-regulated to alter anion secretion and modify disease progressionand/or severity.

Although CFTR transports a variety of molecules in addition to anions,it is clear that this role (the transport of anions) represents oneelement in an important mechanism of transporting ions and water acrossthe epithelium. The other elements include the epithelial Na⁺ channel,ENaC, Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump and the basolateralmembrane K⁺ channels, that are responsible for the uptake of chlorideinto the cell.

These elements work together to achieve directional transport across theepithelium via their selective expression and localization within thecell. Chloride absorption takes place by the coordinated activity ofENaC and CFTR present on the apical membrane and the Na⁺—K⁺-ATPase pumpand Cl-channels expressed on the basolateral surface of the cell.Secondary active transport of chloride from the luminal side leads tothe accumulation of intracellular chloride, which can then passivelyleave the cell via Cl-channels, resulting in a vectorial transport.Arrangement of Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump and thebasolateral membrane K⁺ channels on the basolateral surface and CFTR onthe luminal side coordinate the secretion of chloride via CFTR on theluminal side. Because water is probably never actively transporteditself, its flow across epithelia depends on tiny transepithelialosmotic gradients generated by the bulk flow of sodium and chloride.

In addition to Cystic Fibrosis, modulation of CFTR activity may bebeneficial for other diseases not directly caused by mutations in CFTR,such as secretory diseases and other protein folding diseases mediatedby CFTR. These include, but are not limited to, chronic obstructivepulmonary disease (COPD), dry eye disease, and Sjögren's Syndrome.

COPD is characterized by airflow limitation that is progressive and notfully reversible. The airflow limitation is due to mucus hypersecretion,emphysema, and bronchiolitis. Activators of mutant or wild-type CFTRoffer a potential treatment of mucus hypersecretion and impairedmucociliary clearance that is common in COPD. Specifically, increasinganion secretion across CFTR may facilitate fluid transport into theairway surface liquid to hydrate the mucus and optimized periciliaryfluid viscosity. This would lead to enhanced mucociliary clearance and areduction in the symptoms associated with COPD. Dry eye disease ischaracterized by a decrease in tear aqueous production and abnormal tearfilm lipid, protein and mucin profiles. There are many causes of dryeye, some of which include age, Lasik eye surgery, arthritis,medications, chemical/thermal burns, allergies, and diseases, such asCystic Fibrosis and Sjögrens's syndrome. Increasing anion secretion viaCFTR would enhance fluid transport from the corneal endothelial cellsand secretory glands surrounding the eye to increase corneal hydration.This would help to alleviate the symptoms associated with dry eyedisease. Sjögrens's syndrome is an autoimmune disease in which theimmune system attacks moisture-producing glands throughout the body,including the eye, mouth, skin, respiratory tissue, liver, vagina, andgut. Symptoms, include, dry eye, mouth, and vagina, as well as lungdisease. The disease is also associated with rheumatoid arthritis,systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis.Defective protein trafficking is believed to cause the disease, forwhich treatment options are limited. Modulators of CFTR activity mayhydrate the various organs afflicted by the disease and help to elevatethe associated symptoms.

As discussed above, it is believed that the deletion of residue 508 inΔF508-CFTR prevents the nascent protein from folding correctly,resulting in the inability of this mutant protein to exit the ER, andtraffic to the plasma membrane. As a result, insufficient amounts of themature protein are present at the plasma membrane and chloride transportwithin epithelial tissues is significantly reduced. In fact, thiscellular phenomenon of defective ER processing of ABC transporters bythe ER machinery has been shown to be the underlying basis not only forCF disease, but for a wide range of other isolated and inheriteddiseases. The two ways that the ER machinery can malfunction is eitherby loss of coupling to ER export of the proteins leading to degradation,or by the ER accumulation of these defective/misfolded proteins [AridorM, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B. S., et al.,Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al.,Swiss Med Wkly, 132, pp 211-222 (2002); Morello, J P et al., TIPS, 21,pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198(1999)]. The diseases associated with the first class of ER malfunctionare Cystic fibrosis (due to misfolded ΔF508-CFTR as discussed above),Hereditary emphysema (due to a1-antitrypsin; non Piz variants),Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, suchas Protein C deficiency, Type 1 hereditary angioedema, Lipid processingdeficiencies, such as Familial hypercholesterolemia, Type 1chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, suchas I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses (due to Lysosomalprocessing enzymes), Sandhof/Tay-Sachs (due to β-Hexosaminidase),Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase),Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus (due to Insulinreceptor), Laron dwarfism (due to Growth hormone receptor),Myleoperoxidase deficiency, Primary hypoparathyroidism (due toPreproparathyroid hormone), Melanoma (due to Tyrosinase). The diseasesassociated with the latter class of ER malfunction are Glycanosis CDGtype 1, Hereditary emphysema (due to α1-Antitrypsin (PiZ variant),Congenital hyperthyroidism, Osteogenesis imperfecta (due to Type I, II,IV procollagen), Hereditary hypofibrinogenemia (due to Fibrinogen), ACTdeficiency (due to α1-Antichymotrypsin), Diabetes insipidus (DI),Neurophyseal DI (due to Vasopvessin hormone/V2-receptor), Neprogenic DI(due to Aquaporin II), Charcot-Marie Tooth syndrome (due to Peripheralmyelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease (due to βAPP and presenilins),Parkinson's disease, Amyotrophic lateral sclerosis, Progressivesupranuclear plasy, Pick's disease, several polyglutamine neurologicaldisorders such as Huntington, Spinocerebullar ataxia type I, Spinal andbulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonicdystrophy, as well as Spongiform encephalopathies, such as HereditaryCreutzfeldt-Jakob disease (due to Prion protein processing defect),Fabry disease (due to lysosomal α-galactosidase A) andStraussler-Scheinker syndrome (due to Prp processing defect).

In addition to up-regulation of CFTR activity, reducing anion secretionby CFTR modulators may be beneficial for the treatment of secretorydiarrheas, in which epithelial water transport is dramatically increasedas a result of secretagogue activated chloride transport. The mechanisminvolves elevation of cAMP and stimulation of CFTR.

Although there are numerous causes of diarrhea, the major consequencesof diarrheal diseases, resulting from excessive chloride transport arecommon to all, and include dehydration, acidosis, impaired growth anddeath.

Acute and chronic diarrheas represent a major medical problem in manyareas of the world. Diarrhea is both a significant factor inmalnutrition and the leading cause of death (5,000,000 deaths/year) inchildren less than five years old.

Secretory diarrheas are also a dangerous condition in patients ofacquired immunodeficiency syndrome (AIDS) and chronic inflammatory boweldisease (IBD). 16 million travelers to developing countries fromindustrialized nations every year develop diarrhea, with the severityand number of cases of diarrhea varying depending on the country andarea of travel.

Diarrhea in barn animals and pets such as cows, pigs and horses, sheep,goats, cats and dogs, also known as scours, is a major cause of death inthese animals. Diarrhea can result from any major transition, such asweaning or physical movement, as well as in response to a variety ofbacterial or viral infections and generally occurs within the first fewhours of the animal's life.

The most common diarrhea causing bacteria is enterotoxogenic E-coli(ETEC) having the K99 pilus antigen. Common viral causes of diarrheainclude rotavirus and coronavirus. Other infectious agents includecryptosporidium, giardia lamblia, and salmonella, among others.

Symptoms of rotaviral infection include excretion of watery feces,dehydration and weakness. Coronavirus causes a more severe illness inthe newborn animals, and has a higher mortality rate than rotaviralinfection. Often, however, a young animal may be infected with more thanone virus or with a combination of viral and bacterial microorganisms atone time. This dramatically increases the severity of the disease.

Accordingly, there is a need for modulators of an ABC transporteractivity, and compositions thereof, that can be used to modulate theactivity of the ABC transporter in the cell membrane of a mammal.

There is a need for methods of treating ABC transporter mediateddiseases using such modulators of ABC transporter activity.

There is a need for methods of modulating an ABC transporter activity inan ex vivo cell membrane of a mammal.

There is a need for modulators of CFTR activity that can be used tomodulate the activity of CFTR in the cell membrane of a mammal.

There is a need for methods of treating CFTR-mediated diseases usingsuch modulators of CFTR activity.

There is a need for methods of modulating CFTR activity in an ex vivocell membrane of a mammal.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asmodulators of ABC transporter activity. These compounds have the generalformula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein R₁, R₂,        R₄, ring A, and n are described herein.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, Cysticfibrosis, Hereditary emphysema, Hereditary hemochromatosis,Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency,Type 1 hereditary angioedema, Lipid processing deficiencies, such asFamilial hypercholesterolemia, Type 1 chylomicronemia,Abetalipoproteinemia, Lysosomal storage diseases, such as I-celldisease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetesmellitus, Laron dwarfism, Myleoperoxidase deficiency, Primaryhypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditaryemphysema, Congenital hyperthyroidism, Osteogenesis imperfecta,Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,Perlizaeus-Merzbacher disease, neurodegenerative diseases such asAlzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis,Progressive supranuclear plasy, Pick's disease, several polyglutamineneurological disorders such as Huntington, Spinocerebullar ataxia typeI, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, andMyotonic dystrophy, as well as Spongiform encephalopathies, such asHereditary Creutzfeldt-Jakob disease, Fabry disease,Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren'sdisease.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following definitions shall apply unless otherwiseindicated.

The term “ABC-transporter” as used herein means an ABC-transporterprotein or a fragment thereof comprising at least one binding domain,wherein said protein or fragment thereof is present in vivo or in vitro.The term “binding domain” as used herein means a domain on theABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. etal., J. Gen. Physiol. (1998): 111(3), 477-90.

The term “CFTR” as used herein means cystic fibrosis transmembraneconductance regulator or a mutation thereof capable of regulatoractivity, including, but not limited to, ΔF508 CFTR and G551D CFTR (see,e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).

The term “modulating” as used herein means increasing or decreasing,e.g. activity, by a measurable amount. Compounds that modulate ABCTransporter activity, such as CFTR activity, by increasing the activityof the ABC Transporter, e.g., a CFTR anion channel, are called agonists.Compounds that modulate ABC Transporter activity, such as CFTR activity,by decreasing the activity of the ABC Transporter, e.g., CFTR anionchannel, are called antagonists. An agonist interacts with an ABCTransporter, such as CFTR anion channel, to increase the ability of thereceptor to transduce an intracellular signal in response to endogenousligand binding. An antagonist interacts with an ABC Transporter, such asCFTR, and competes with the endogenous ligand(s) or substrate(s) forbinding site(s) on the receptor to decrease the ability of the receptorto transduce an intracellular signal in response to endogenous ligandbinding.

The phrase “treating or reducing the severity of an ABC Transportermediated disease” refers both to treatments for diseases that aredirectly caused by ABC Transporter and/or CFTR activities andalleviation of symptoms of diseases not directly caused by ABCTransporter and/or CFTR anion channel activities. Examples of diseaseswhose symptoms may be affected by ABC Transporter and/or CFTR activityinclude, but are not limited to, Cystic fibrosis, Hereditary emphysema,Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, suchas Protein C deficiency, Type 1 hereditary angioedema, Lipid processingdeficiencies, such as Familial hypercholesterolemia, Type 1chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, suchas I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism,Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma,Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism,Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency,Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-MarieTooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Progressive supranuclear plasy, Pick's disease,several polyglutamine neurological disorders such as Huntington,Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,Dentatorubal pallidoluysian, and Myotonic dystrophy, as well asSpongiform encephalopathies, such as Hereditary Creutzfeldt-Jakobdisease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eyedisease, and Sjogren's disease.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausolito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As used herein the term “aliphatic’ encompasses the terms alkyl,alkenyl, alkynyl, each of which being optionally substituted as setforth below.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. Analkyl group can be straight or branched. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or2-ethylhexyl. An alkyl group can be substituted (i.e., optionallysubstituted) with one or more substituents such as halo, cycloaliphatic[e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g.,heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy,aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl,(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro,cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino], amino [e.g., aliphaticamino,cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g.,aliphaticsulfonyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy,heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Withoutlimitation, some examples of substituted alkyls include carboxyalkyl(such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl),cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, hydroxyalkyl, aralkyl,(alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as(alkylsulfonylamino)alkyl), aminoalkyl, amidoalkyl,(cycloaliphatic)alkyl, cyanoalkyl, or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least onedouble bond. Like an alkyl group, an alkenyl group can be straight orbranched. Examples of an alkenyl group include, but are not limited to,allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can beoptionally substituted with one or more substituents such as halo,cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, alkoxy, aroyl,heteroaroyl, acyl [e.g., (cycloaliphatic)carbonyl, or(heterocycloaliphatic)carbonyl], nitro, cyano, acyl [e.g.,aliphaticcarbonyl, cycloaliphaticcarbonyl, arylcarbonyl,heterocycloaliphaticcarbonyl or heteroarylcarbonyl], amido [e.g.,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,aliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g.,alkylsulfonyl, cycloaliphaticsulfonyl, or arylsulfonyl], sulfinyl,sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy,carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy,heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl,alkylcarbonyloxy, or hydroxy.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least onetriple bond. An alkynyl group can be straight or branched. Examples ofan alkynyl group include, but are not limited to, propargyl and butynyl.An alkynyl group can be optionally substituted with one or moresubstituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy,cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanylor cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl orcycloaliphaticsulfinyl], sulfonyl [e.g., aliphaticsulfonyl,aliphaticaminosulfonyl, or cycloaliphaticsulfonyl], amido [e.g.,aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, acyl [e.g.,(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino[e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

As used herein, an “amido” encompasses both “aminocarbonyl” and“carbonylamino”. These terms when used alone or in connection withanother group refers to an amido group such as N(R^(X))₂—C(O)— orR^(Y)C(O)—N(R^(X))— when used terminally and —C(O)—N(R^(X))— or—N(R^(X))—C(O)— when used internally, wherein R^(X) and R^(Y) aredefined below. Examples of amido groups include alkylamido (such asalkylcarbonylamino or alkylcarbonylamino), (heterocycloaliphatic)amido,(heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido,arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each ofR^(X) and R^(Y) is independently hydrogen, alkyl, cycloaliphatic,(cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl,sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl,((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or(heteroaraliphatic)carbonyl, each of which being defined herein andbeing optionally substituted. Examples of amino groups includealkylamino, dialkylamino, or arylamino. When the term “amino” is not aterminal group (e.g., alkylcarbonylamino), it is represented by—NR^(X)—. R^(X) has the same meaning as defined above.

As used herein, an “aryl” group used alone or as part of a larger moietyas in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic(e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl,tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyltetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systemsin which the monocyclic ring system is aromatic or at least one of therings in a bicyclic or tricyclic ring system is aromatic. The bicyclicand tricyclic groups include benzofused 2-3 membered carbocyclic rings.For example, a benzofused group includes phenyl fused with two or moreC₄₋₈ carbocyclic moieties. An aryl is optionally substituted with one ormore substituents including aliphatic [e.g., alkyl, alkenyl, oralkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of abenzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl[e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl;((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;(heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl oraminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl orcycloaliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanyl]; cyano;halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide;or carbamoyl. Alternatively, an aryl can be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [e.g.,mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl[e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and(alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl,(((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl,(arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl];aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,(aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;(((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl;((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl;(alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl;p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl;or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

As used herein, an “araliphatic” such as an “aralkyl” group refers to analiphatic group (e.g., a C₁₋₄ alkyl group) that is substituted with anaryl group. “Aliphatic,” “alkyl,” and “aryl” are defined herein. Anexample of an araliphatic such as an aralkyl group is benzyl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., aC₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl”and “aryl” have been defined above. An example of an aralkyl group isbenzyl. An aralkyl is optionally substituted with one or moresubstituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl,including carboxyalkyl, hydroxyalkyl, or haloalkyl such astrifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or11) membered structures that form two rings, wherein the two rings haveat least one atom in common (e.g., 2 atoms in common). Bicyclic ringsystems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclicheteroaryls.

As used herein, a “cycloaliphatic” group encompasses a “cycloalkyl”group and a “cycloalkenyl” group, each of which being optionallysubstituted as set forth below.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclicmono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbonatoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl,octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl,bicyclo[2.2.2]octyl, adamantyl, azacycloalkyl, or((aminocarbonyl)cycloalkyl)cycloalkyl. A “cycloalkenyl” group, as usedherein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8)carbon atoms having one or more double bonds. Examples of cycloalkenylgroups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl,cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl,cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl. Acycloalkyl or cycloalkenyl group can be optionally substituted with oneor more substituents such as aliphatic [e.g., alkyl, alkenyl, oralkynyl], cycloaliphatic, (cycloaliphatic) aliphatic,heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl,heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy,aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino,(aryl)carbonylamino, (araliphatic)carbonylamino,(heterocycloaliphatic)carbonylamino,((heterocycloaliphatic)aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl[e.g., alkylsulfonyl and arylsulfonyl], sulfinyl [e.g., alkylsulfinyl],sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, or carbamoyl.

As used herein, “cyclic moiety” includes cycloaliphatic,heterocycloaliphatic, aryl, or heteroaryl, each of which has beendefined previously.

As used herein, the term “heterocyclic” encompasses aheterocycloaliphatic group and a heteroaryl group.

As used herein, the term “heterocycloaliphatic” encompasses aheterocycloalkyl group and a heterocycloalkenyl group, each of whichbeing optionally substituted as set forth below.

As used herein, a “heterocycloalkyl” group refers to a 3-10 memberedmono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- orbicyclic) saturated ring structure, in which one or more of the ringatoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examplesof a heterocycloalkyl group include piperidyl, piperazyl,tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl,1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl,octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl,octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl,octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. A monocyclic heterocycloalkylgroup can be fused with a phenyl moiety such as tetrahydroisoquinoline.A “heterocycloalkenyl” group, as used herein, refers to a mono- orbicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ringstructure having one or more double bonds, and wherein one or more ofthe ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic andbicycloheteroaliphatics are numbered according to standard chemicalnomenclature.

A heterocycloalkyl or heterocycloalkenyl group can be optionallysubstituted with one or more substituents such as aliphatic [e.g.,alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic,heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl,alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino,(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,((heterocycloaliphatic) aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto,sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g.,alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system having 4 to 15 ring atoms wherein one or moreof the ring atoms is a heteroatom (e.g., N, O, S, or combinationsthereof) and in which the monocyclic ring system is aromatic or at leastone of the rings in the bicyclic or tricyclic ring systems is aromatic.A heteroaryl group includes a benzofused ring system having 2 to 3rings. For example, a benzofused group includes benzo fused with one ortwo 3-8 membered heterocycloaliphatic moieties (e.g., indolizyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples ofheteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl,isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine,dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl,indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl,quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl,4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophenyl,2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl,pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.Monocyclic heteroaryls are numbered according to standard chemicalnomenclature.

Without limitation, bicyclic heteroaryls include indolizyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl,quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl,benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazyl,benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl,phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.Bicyclic heteroaryls are numbered according to standard chemicalnomenclature.

A heteroaryl is optionally substituted with one or more substituentssuch as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;(cycloaliphatic)aliphatic; heterocycloaliphatic;(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy;(araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo(on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic ortricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphaticcarbonyl;(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl oraminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g.,aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, aheteroaryl can be unsubstituted.

Non-limiting examples of substituted heteroaryls include(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl;aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g.,aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl,((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,(((heteroaryl)amino)carbonyl)heteroaryl,((heterocycloaliphatic)carbonyl)heteroaryl, and((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;(alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;((carboxy)alkyl)heteroaryl; [((dialkyl)amino)alkyl]heteroaryl;(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;(nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl;((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl;(acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl,and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

A “heteroaraliphatic” (such as a heteroaralkyl group) as used herein,refers to an aliphatic group (e.g., a C₁₋₄ alkyl group) that issubstituted with a heteroaryl group. “Aliphatic,” “alkyl,” and“heteroaryl” have been defined above.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g.,a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both“alkyl” and “heteroaryl” have been defined above. A heteroaralkyl isoptionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, “cyclic moiety” includes cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which hasbeen defined previously.

As used herein, an “acyl” group refers to a formyl group or R^(X)—C(O)—(such as -alkyl-C(O)—, also referred to as “alkylcarbonyl”) where R^(X)and “alkyl” have been defined previously. Acetyl and pivaloyl areexamples of acyl groups.

As used herein, an “aroyl” or “heteroaroyl” refers to an aryl-C(O)— or aheteroaryl-C(O)—. The aryl and heteroaryl portion of the aroyl orheteroaroyl is optionally substituted as previously defined.

As used herein, an “alkoxy” group refers to an alkyl-O— group where“alkyl” has been defined previously.

As used herein, a “carbamoyl” group refers to a group having thestructure —O—CO—NR^(X)R^(Y) or —NR^(X)—CO—O—R^(Z) wherein R^(X) andR^(Y) have been defined above and R^(Z) can be aliphatic, aryl,araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

As used herein, a “carboxy” group refers to —COOH, —COOR^(X), —OC(O)H,—OC(O)R^(X) when used as a terminal group; or —OC(O)— or —C(O)O— whenused as an internal group.

As used herein, a “haloaliphatic” group refers to an aliphatic groupsubstituted with 1, 2, or 3 halogen atoms. For instance, the termhaloalkyl includes the group —CF₃.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfo” group refers to —SO₃H or —SO₃R^(X) when usedterminally or —S(O)₃— when used internally.

As used herein, a “sulfamide” group refers to the structure—NR^(X)—S(O)₂—NR^(Y)R^(Z) when used terminally and —NR^(X)—S(O)₂—NR^(Y)—when used internally, wherein R^(X), R^(Y), and R^(Z) have been definedabove.

As used herein, a “sulfamoyl” group refers to the structure—S(O)₂—NR^(X)R^(Y) or —NR^(X)—S(O)₂—R^(Z) when used terminally; or—S(O)₂—NR^(X)— or —NR^(X)—S(O)₂— when used internally, wherein R^(X),R^(Y), and R^(Z) are defined above.

As used herein a “sulfanyl” group refers to —S—R^(X) when usedterminally and —S— when used internally, wherein R^(X) has been definedabove. Examples of sulfanyls include alkylsulfanyl.

As used herein a “sulfinyl” group refers to —S(O)—R^(X) when usedterminally and —S(O)—when used internally, wherein R^(X) has beendefined above.

As used herein, a “sulfonyl” group refers to —S(O)₂—R^(X) when usedterminally and —S(O)₂— when used internally, wherein R^(X) has beendefined above.

As used herein, a “sulfoxy” group refers to —O—SO—R^(X) or —SO—O—R^(X),when used terminally and —O—S(O)— or —S(O)—O— when used internally,where R^(X) has been defined above.

As used herein, a “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, an “alkoxycarbonyl,” which is encompassed by the termcarboxy, used alone or in connection with another group refers to agroup such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such asalkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, a “carbonyl” refer to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, an “aminoalkyl” refers to the structureR^(X)R^(Y)N-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (NC)-alkyl-.

As used herein, a “urea” group refers to the structure—NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure—NR^(X)—CS—NR^(Y)R^(Z) when used terminally and —NR^(X)—CO—NR^(Y)— or—NR^(X)—CS—NR^(Y)— when used internally, wherein R^(X), R^(Y), and R^(Z)have been defined above.

As used herein, a “guanidino” group refers to the structure—N═C(N(R^(X)R^(Y)))N(R^(X)R^(Y)) wherein R^(X) and R^(Y) have beendefined above.

As used herein, the term “amidino” group refers to the structure—C═(NR^(X))N(R^(X)R^(Y)) wherein R^(X) and R^(Y) have been definedabove.

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O(O)C-alkyl is an exampleof a carboxy group used terminally. A group is internal when the groupis present in the middle of a substituent to at the end of thesubstituent bound to the rest of the chemical structure. Alkylcarboxy(e.g., alkyl-C(O)O— or alkyl-OC(O)—) and alkylcarboxyaryl (e.g.,alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groupsused internally.

As used herein, “cyclic group” includes mono-, bi-, and tri-cyclic ringsystems including cycloaliphatic, heterocycloaliphatic, aryl, orheteroaryl, each of which has been previously defined.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocyclicalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system canbe optionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, an “aliphatic chain” refers to a branched or straightaliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).A straight aliphatic chain has the structure —[CH₂]_(v)—, where v is1-6. A branched aliphatic chain is a straight aliphatic chain that issubstituted with one or more aliphatic groups. A branched aliphaticchain has the structure —[CHQ]_(v)- where Q is hydrogen or an aliphaticgroup; however, Q shall be an aliphatic group in at least one instance.The term aliphatic chain includes alkyl chains, alkenyl chains, andalkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted.” As described herein, compounds ofthe invention can optionally be substituted with one or moresubstituents, such as are illustrated generally above, or as exemplifiedby particular classes, subclasses, and species of the invention. Asdescribed herein, the variables R₁, R₂, R₃, and R₄, and other variablescontained therein formulae I encompass specific groups, such as alkyland aryl. Unless otherwise noted, each of the specific groups for thevariables R₁, R₂, R₃, and R₄, and other variables contained therein canbe optionally substituted with one or more substituents describedherein. Each substituent of a specific group is further optionallysubstituted with one to three of halo, cyano, oxoalkoxy, hydroxy, amino,nitro, aryl, haloalkyl, and alkyl. For instance, an alkyl group can besubstituted with alkylsulfanyl and the alkylsulfanyl can be optionallysubstituted with one to three of halo, cyano, oxoalkoxy, hydroxy, amino,nitro, aryl, haloalkyl, and alkyl. As an additional example, thecycloalkyl portion of a (cycloalkyl)carbonylamino can be optionallysubstituted with one to three of halo, cyano, alkoxy, hydroxy, nitro,haloalkyl, and alkyl. When two alkoxy groups are bound to the same atomor adjacent atoms, the two alkoxy groups can form a ring together withthe atom(s) to which they are bound.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent independently selected from a specified group, thesubstituent can be either the same or different at every position. Aring substituent, such as a heterocycloalkyl, can be bound to anotherring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g.,both rings share one common atom. As one of ordinary skill in the artwill recognize, combinations of substituents envisioned by thisinvention are those combinations that result in the formation of stableor chemically feasible compounds.

The phrase “up to” as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3.

The phrase “stable or chemically feasible,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, an effective amount is defined as the amount required toconfer a therapeutic effect on the treated patient, and is typicallydetermined based on age, surface area, weight, and condition of thepatient. The interrelationship of dosages for animals and humans (basedon milligrams per meter squared of body surface) is described byFreireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surfacearea may be approximately determined from height and weight of thepatient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley,N.Y., 537 (1970). As used herein, “patient” refers to a mammal,including a human.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C— or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

Compounds

Compounds of the present invention are useful modulators of ABCtransporters and are useful in the treatment of ABC transporter mediateddiseases.

A. Generic Compounds

The present invention includes a compound of formula I,

-   -   or a pharmaceutically acceptable salt thereof.

A method of modulating the number of functional ABC transporters in amembrane of a cell comprising the step of contacting said cell with acompound of formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:

Each R₁ is an optionally substituted C₁₋₆ aliphatic, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted C₃₋₁₀ cycloaliphatic, or an optionally substituted 4 to 10membered heterocycloaliphatic, carboxy [e.g., hydroxycarbonyl oralkoxycarbonyl], alkoxy, amido [e.g., aminocarbonyl], amino, halo,cyano, alkylsulfanyl, or hydroxy;

provided that at least one R₁ is an optionally substituted aryl or anoptionally substituted heteroaryl and said R₁ is attached to the 3- or4-position of the phenyl ring;

Each R₂ is hydrogen, an optionally substituted C₁₋₆ aliphatic, anoptionally substituted C₃₋₆ cycloaliphatic, an optionally substitutedphenyl, or an optionally substituted heteroaryl;

Each R₄ is an optionally substituted aryl or an optionally substitutedheteroaryl;

Each n is 1, 2, 3, 4 or 5; and

Ring A is an optionally substituted cycloaliphatic or an optionallysubstituted heterocycloaliphatic where the atoms of ring A adjacent toC* are carbon atoms, and each of which is optionally substituted with 1,2, or 3 substituents.

B. Specific Embodiments

1. Substituent R₁

Each R₁ is an optionally substituted C₁₋₆ aliphatic, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted C₃₋₁₀ cycloaliphatic, an optionally substituted 4 to 10membered heterocycloaliphatic, carboxy [e.g., hydroxycarbonyl oralkoxycarbonyl], amido [e.g., aminocarbonyl], amino, halo, alkoxy, orhydroxy.

In some embodiments, one R₁ is an optionally substituted C₁₋₆ aliphatic.In several examples, one R₁ is an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, or an optionally substituted C₂₋₆alkynyl. In several examples, one R₁ is C₁₋₆ alkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl.

In several embodiments, one R₁ is an aryl or heteroaryl with 1, 2, or 3substituents. In several examples, one R₁ is a monocyclic aryl orheteroaryl. In several embodiments, R₁ is an aryl or heteroaryl with 1,2, or 3 substituents. In several examples, R₁ is a monocyclic aryl orheteroaryl.

In several embodiments, at least one R₁ is an optionally substitutedaryl or an optionally substituted heteroaryl and R₁ is bonded to thecore structure at the 4-position on the phenyl ring.

In several embodiments, at least one R₁ is an optionally substitutedaryl or an optionally substituted heteroaryl and R₁ is bonded to thecore structure at the 3-position on the phenyl ring.

In several embodiments, one R₁ is phenyl with up to 3 substituents. Inseveral embodiments, R₁ is phenyl with up to 2 substituents.

In several embodiments, one R₁ is a heteroaryl ring with up to 3substituents. In certain embodiments, one R₁ is a monocyclic heteroarylring with up to 3 substituents. In other embodiments, one R₁ is abicyclic heteroaryl ring with up to 3 substituents. In severalembodiments, R₁ is a heteroaryl ring with up to 3 substituents.

In some embodiments, one R₁ is an optionally substituted C₃₋₁₀cycloaliphatic or an optionally substituted 3-8 memberedheterocycloaliphatic. In several examples, one R₁ is a monocycliccycloaliphatic substituted with up to 3 substituents. In severalexamples, one R₁ is a monocyclic heterocycloaliphatic substituted withup to 3 substituents. In one embodiment, one R₁ is a 4 memberedheterocycloaliphatic having one ring member selected from oxygen,nitrogen (including NH and NR^(X)), or sulfur (including S, SO, andSO₂); wherein said heterocycloaliphatic is substituted with up to 3substitutents. In one example, one R₁ is 3-methyloxetan-3-yl.

In several embodiments, one R₁ is carboxy [e.g., hydroxycarbonyl oralkoxycarbonyl]. Or, one R₁ is amido [e.g., aminocarbonyl]. Or, one R₁is amino. Or, is halo. Or, is cyano. Or, hydroxy.

In some embodiments, R₁ is hydrogen, methyl, ethyl, iso-propyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, F,Cl, methoxy, ethoxy, iso-propoxy, tert-butoxy, CF₃, OCF₃, SCH₃, SCH₂CH₃,CN, hydroxy, or amino. In several examples, R₁ is hydrogen, methyl,ethyl, iso-propyl, tert-butyl, methoxy, ethoxy, SCH₃, SCH₂CH₃, F, Cl,CF₃, or OCF₃. In several examples, R₁ can be hydrogen. Or, R₁ can bemethyl. Or, R₁ can be ethyl. Or, R₁ can be iso-propyl. Or, R₁ can betert-butyl. Or, R₁ can be F. Or, R₁ can be Cl. Or, R₁ can be OH. Or, R₁can be OCF₃. Or, R₁ can be CF₃. Or, R₁ can be methoxy. Or, R₁ can beethoxy. Or, R₁ can be SCH₃.

In several embodiments, R₁ is substituted with no more than threesubstituents independently selected from halo, oxo, or optionallysubstituted aliphatic, cycloaliphatic, heterocycloaliphatic, amino[e.g., (aliphatic)amino], amido [e.g., aminocarbonyl,((aliphatic)amino)carbonyl, and ((aliphatic)₂amino)carbonyl], carboxy[e.g., alkoxycarbonyl and hydroxycarbonyl], sulfamoyl [e.g.,aminosulfonyl, ((aliphatic)₂amino)sulfonyl,((cycloaliphatic)aliphatic)aminosulfonyl, and((cycloaliphatic)amino)sulfonyl], cyano, alkoxy, aryl, heteroaryl [e.g.,monocyclic heteroaryl and bicycloheteroaryl], sulfonyl [e.g.,aliphaticsulfonyl or (heterocycloaliphatic)sulfonyl], sulfinyl [e.g.,aliphaticsulfinyl], aroyl, heteroaroyl, or heterocycloaliphaticcarbonyl.

In several embodiments, R₁ is substituted with halo. Examples of R₁substituents include F, Cl, and Br. In several examples, R₁ issubstituted with F.

In several embodiments, R₁ is substituted with an optionally substitutedaliphatic. Examples of R₁ substituents include optionally substitutedalkoxyaliphatic, heterocycloaliphatic, aminoalkyl, hydroxyalkyl,(heterocycloalkyl)aliphatic, alkylsulfonylaliphatic,alkylsulfonylaminoaliphatic, alkylcarbonylaminoaliphatic,alkylaminoaliphatic, or alkylcarbonylaliphatic.

In several embodiments, R₁ is substituted with an optionally substitutedamino. Examples of R₁ substituents include aliphaticcarbonylamino,aliphaticamino, arylamino, or aliphaticsulfonylamino.

In several embodiments, R₁ is substituted with a sulfonyl. Examples ofR₁ include heterocycloaliphatic sulfonyl, aliphatic sulfonyl,aliphaticaminosulfonyl, aminosulfonyl, aliphaticcarbonylaminosulfonyl,alkoxyalkylheterocycloalkylsulfonyl, alkylheterocycloalkylsulfonyl,alkylaminosulfonyl, cycloalkylaminosulfonyl,(heterocycloalkyl)alkylaminosulfonyl, and heterocycloalkylsulfonyl.

In several embodiments, R₁ is substituted with carboxy. Examples of R₁substituents include alkoxycarbonyl and hydroxycarbonyl.

In several embodiments R₁ is substituted with amido. Examples of R₁substituents include alkylaminocarbonyl, aminocarbonyl,((aliphatic)₂amino)carbonyl, and[((aliphatic)aminoaliphatic)amino]carbonyl.

In several embodiments, R₁ is substituted with carbonyl. Examples of R₁substituents include arylcarbonyl, cycloaliphaticcarbonyl,heterocycloaliphaticcarbonyl, and heteroarylcarbonyl.

In several embodiments, each R₁ is a hydroxycarbonyl, hydroxy, or halo.

In some embodiments, R₁ is hydrogen. In some embodiments, R₁ is-Z^(E)R₉, wherein each Z^(E) is independently a bond or an optionallysubstituted branched or straight C₁₋₆ aliphatic chain wherein up to twocarbon units of Z^(E) are optionally and independently replaced by —CO—,—CS—, —CONR^(E)—, —CONR^(E)NR^(E)—, —CO₂—, —OCO—, —NR^(E)CO₂—, —O—,—NR^(E)CONR^(E)—, —OCONR^(E)—, —NR^(E)NR^(E)—, —NR^(E)CO—, —S—, —SO—,—SO₂—, —NR^(E)—, —SO₂NR^(E)—, —NR^(E)SO₂—, or —NR^(E)SO₂NR^(E)—. Each R₉is hydrogen, R^(E), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃. EachR^(E) is independently a C₁₋₈ aliphatic group, a cycloaliphatic, aheterocycloaliphatic, an aryl, or a heteroaryl, each of which isoptionally substituted with 1, 2, or 3 of R^(A). Each R^(A) is -Z^(A)R₅,wherein each Z^(A) is independently a bond or an optionally substitutedbranched or straight C₁₋₆ aliphatic chain wherein up to two carbon unitsof Z^(A) are optionally and independently replaced by —CO—, —CS—,—CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—,—NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—,—SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—. Each R₅is independently R^(B), halo, —B(OH)₂, —OH, —NH₂, —NO₂, —CN, —CF₃, or—OCF₃. Each R^(B) is independently hydrogen, an optionally substitutedC₁₋₈ aliphatic group, an optionally substituted cycloaliphatic, anoptionally substituted heterocycloaliphatic, an optionally substitutedaryl, or an optionally substituted heteroaryl.

In several embodiments, R₁ is -Z^(E)R₉, wherein each Z^(E) isindependently a bond or an optionally substituted branched or straightC₁₋₆ aliphatic chain wherein up to two carbon units of Z^(E) areoptionally and independently replaced by —CO—, —CONR^(E)—, —CO₂—, —O—,—S—, —SO—, —SO₂—, —NR^(E)—, or —SO₂NR^(E)—. Each R₉ is hydrogen, R^(E),halo, —OH, —NH₂, —CN, —CF₃, or —OCF₃. Each R^(E) is independently anoptionally substituted group selected from C₁₋₈ aliphatic group,cycloaliphatic, heterocycloaliphatic, aryl, and heteroaryl. In oneembodiment, Z^(E) is a bond. In one embodiment, Z^(E) is a straight C₁₋₆aliphatic chain, wherein one carbon unit of Z^(E) is optionally replacedby —CO—, —CONR^(E)—, —CO₂—, —O—, or —NR^(E)—. In one embodiment, Z^(E)is a C₁₋₆ alkyl chain. In one embodiment, Z^(E) is —CH₂—. In oneembodiment, Z^(E) is —CO—. In one embodiment, Z^(E) is —CO₂—. In oneembodiment, Z^(E) is —CONR^(E)—.

In some embodiments, R₉ is H, —NH₂, hydroxy, —CN, or an optionallysubstituted group selected from C₁₋₈ aliphatic, C₃₋₈ cycloaliphatic, 3-8membered heterocycloaliphatic, C₆₋₁₀ aryl, and 5-10 membered heteroaryl.In one embodiment, R₉ is H. In one embodiment, R₉ is hydroxy. Or, R₉ is—NH₂. Or, R₉ is —CN. In some embodiments, R₉ is an optionallysubstituted 3-8 membered heterocycloaliphatic, having 1, 2, or 3 ringmembers independently selected from nitrogen (including NH and NR^(X)),oxygen, and sulfur (including S, SO, and SO₂). In one embodiment, R₉ isan optionally substituted five membered heterocycloaliphatic with onenitrogen (including NH and NR^(X)) ring member. In one embodiment, R₉ isan optionally substituted pyrrolidin-1-yl. Examples of said optionallysubstituted pyrrolidin-1-yl include pyrrolidin-1-yl and3-hydroxy-pyrrolidin-1-yl. In one embodiment, R₉ is an optionallysubstituted six membered heterocycloaliphatic with two heteroatomsindependently selected from nitrogen (including NH and NR^(X)) andoxygen. In one embodiment, R₉ is morpholin-4-yl. In some embodiments, R₉is an optionally substituted 5-10 membered heteroaryl. In oneembodiment, R₉ is an optionally substituted 5 membered heteroaryl,having 1, 2, 3, or 4 ring members independently selected from nitrogen(including NH and NR^(X)), oxygen, and sulfur (including S, SO, andSO₂). In one embodiment, R₉ is 1H-tetrazol-5-yl.

In one embodiment, one R₁ is Z^(E)R₉; wherein Z^(E) is CH₂ and R₉ is1H-tetrazol-5-yl. In one embodiment, one R₁ is Z^(E)R₉; wherein Z^(E) isCH₂ and R₉ is morpholin-4-yl. In one embodiment, one R₁ is Z^(E)R₉;wherein Z^(E) is CH₂ and R₉ is pyrrolidin-1-yl. In one embodiment, oneR₁ is Z^(E)R₉; wherein Z^(E) is CH₂ and R₉ is 3-hydroxy-pyrrolidin-1-yl.In one embodiment, one R₁ is Z^(E)R₉; wherein Z^(E) is CO and R₉ is3-hydroxy-pyrrolidin-1-yl.

In some embodiments, R₁ is selected from CH₂OH, COOH, CH₂OCH₃, COOCH₃,CH₂NH₂, CH₂NHCH₃, CH₂CN, CONHCH₃, CH₂CONH₂, CH₂OCH₂CH₃, CH₂N(CH₃)₂,CON(CH₃)₂, CH₂NHCH₂CH₂OH, CH₂NHCH₂CH₂COOH, CH₂OCH(CH₃)₂,CONHCH(CH₃)CH₂OH, or CONHCH(tert-butyl)CH₂OH.

In several embodiments, R₁ is halo, or R₁ is C₁₋₆ aliphatic, aryl,heteroaryl, alkoxy, cycloaliphatic, heterocycloaliphatic, each of whichis optionally substituted with 1, 2, or 3 of R^(A); or R₁ is halo;wherein each R^(A) is -Z^(A)R₅, each Z^(A) is independently a bond or anoptionally substituted branched or straight C₁₋₆ aliphatic chain whereinup to two carbon units of Z^(A) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—,—NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—,—NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or—NR^(B)SO₂NR^(B)—; each R₅ is independently R^(B), halo, —B(OH)₂, —OH,—NH₂, —NO₂, —CN, —CF₃, or —OCF₃; and each R^(B) is hydrogen, optionallysubstituted C₁₋₄ aliphatic, optionally substituted C₃₋₆ cycloaliphatic,optionally substituted heterocycloaliphatic, optionally substitutedphenyl, or optionally substituted heteroaryl.

In some embodiments, Z^(A) is independently a bond or an optionallysubstituted branched or straight C₁₋₆ aliphatic chain wherein up to twocarbon units of Z^(A) are optionally and independently replaced by —CO—,—CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—,—NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—,—SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—. In oneembodiment, Z^(A) is a bond. In some embodiments, Z^(A) is an optionallysubstituted straight or branched C₁₋₆ aliphatic chain wherein up to twocarbonunites of Z^(A) are optionally and independently replaced by —CO—,—CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—,—NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—,—SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—. In oneembodiment, Z^(A) is an optionally substituted straight or branched C₁₋₆alkyl chain wherein up to two carbon units of Z^(A) is optionallyreplaced by —O—, —NHC(O)—, —C(O)NR^(B)—, —SO₂—, —NHSO₂—, —NHC(O)—, —SO—,—NR^(B)SO₂—, —SO₂NH—, —SO₂NR^(B)—, —NH—, or —C(O)O—. In one embodiment,Z^(A) is an optionally substituted straight or branched C₁₋₆ alkyl chainwherein one carbon unit of Z^(A) is optionally replaced by —O—,—NHC(O)—, —C(O)NR^(B)—, —SO₂—, —NHSO₂—, —NHC(O)—, —SO—, —NR^(B)SO₂—,—SO₂NH—, —SO₂NR^(B)—, —NH—, or —C(O)O—. In one embodiment, Z^(A) is anoptionally substituted straight or branched C₁₋₆ alkyl chain wherein onecarbon unit of Z^(A) is optionally replaced by —CO—, —CONR^(B)—, —CO₂—,—O—, —NR^(B)CO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, or —NR^(B)SO₂—. In oneembodiment, Z^(A) is an optionally substituted straight or branched C₁₋₆alkyl chain wherein one carbon unit of Z^(A) is optionally replaced by—SO₂—, —CONR^(B)—, or —SO₂NR^(B)—. In one embodiment, Z^(A) is —CH₂— or—CH₂CH₂—. In one embodiment, Z^(A) is an optionally substituted straightor branched C₁₋₆ alkyl chain wherein one carbon unit of Z^(A) isoptionally replaced by —CO—, —CONR^(B)—, —CO₂—, —O—, —NHCO—, —SO—,—SO₂—, —NR^(B)—, —SO₂NR^(B)—, or —NR^(B)SO₂—. In some embodiments, Z^(A)is —CO₂—, —CH₂CO₂—, —CH₂CH₂CO₂—, —CH(NH₂)CH₂CO₂—, or —CH(CH₃)CH₂CO₂—. Insome embodiments, Z^(A) is —CONH—, —NHCO—, or —CON(CH₃)—. In someembodiments, Z^(A) is —O—. Or, Z^(A) is —SO—, —SO₂—, —SO₂NH—, or—SO₂N(CH₃). In one embodiment, Z^(A) is an optionally substitutedbranched or straight C₁₋₆ aliphatic chain wherein one carbon unit ofZ^(A) is optionally replaced by —SO₂—.

In some embodiments, R₅ is H, F, Cl, —B(OH)₂, —OH, —NH₂, —CF₃, —OCF₃, or—CN. In one embodiment, R₅ is H. Or, R₅ is F. Or, R₅ is Cl. Or, R₅ is—B(OH)₂. Or, R₅ is —OH. Or, R₅ is —NH₂. Or, R₅ is —CF₃. Or, R₅ is —OCF₃.Or, R₅ is —CN.

In some embodiments, R₅ is an optionally substituted C₁₋₄ aliphatic. Inone embodiment, R₅ is an optionally substituted C₁₋₄ alkyl. In oneembodiment, R₅ is methyl, ethyl, iso-propyl, or tert-butyl. In oneembodiment, R₅ is an optionally substituted aryl. In one embodiment, R₅is an optionally substituted phenyl. In some embodiments, R₅ is anoptionally substituted heteroaryl or an optionally substitutedheterocycloaliphatic. In some embodiments, R₅ is an optionallysubstituted heteroaryl. In one embodiment, R₅ is an optionallysubstituted monocyclic heteroaryl, having 1, 2, 3, or 4 ring membersoptionally and independently replaced with nitrogen (including NH andNR^(X)), oxygen or sulfur (including S, SO, and SO₂). In one embodiment,R₅ is an optionally substituted 5 membered heteroaryl. In oneembodiment, R₅ is 1H-tetrazol-5-yl. In one embodiment, R₅ is anoptionally substituted bicylic heteroaryl. In one embodiment, R₅ is a1,3-dioxoisoindolin-2-yl. In some embodiments, R₅ is an optionallysubstituted heterocycloaliphatic having 1 or 2 nitrogen (including NHand NR^(X)) atoms and R₅ attaches directly to —SO₂— via one ringnitrogen.

In some embodiments, two occurrences of R^(A), taken together withcarbon atoms to which they are attached, form an optionally substituted3-8 membered saturated, partially unsaturated, or aromatic ring, havingup to 4 ring members optionally and independently replaced with nitrogen(including NH and NR^(X)), oxygen, or sulfur (including S, SO, and SO₂).In some embodiments, two occurrences of R^(A), taken together withcarbon atoms to which they are attached, form C₄₋₈ cycloaliphatic ringoptionally substituted with 1, 2, or 3 substituents independentlyselected from oxo, ═NR^(B), ═N—N(R^(B))₂, halo, CN, CO₂, CF₃, OCF₃, OH,SR^(B), S(O)R_(B), SO₂R^(B), NH₂, NHR^(B), N(R^(B))₂, COOH, COOR^(B),OR^(B), or R^(B). In one embodiment, said cycloaliphatic ring issubstituted with oxo. In one embodiment, said cycloaliphatic ring is

In some embodiments, two occurrences of R^(A), taken together withcarbon atoms to which they are attached, form an optionally substituted5-8 membered heterocycloaliphatic ring, having up to 4 ring membersoptionally and independently replaced with nitrogen (including NH andNR^(X)), oxygen, or sulfur (including S, SO, and SO₂). In someembodiments, two occurrences of R^(A), taken together with carbon atomsto which they are attached, form a 5 or 6 membered heterocycloaliphaticring, optionally substituted with 1, 2, or 3 substituents independentlyselected from oxo, ═NR^(B), ═N—N(R^(B))₂, halo, CN, CO₂, CF₃, OCF₃, OH,SR^(B), S(O)R^(B), SO₂R^(B), NH₂, NHR^(B), N(R^(B))₂, COOH, COOR^(B),OR^(B), or R^(B). In some embodiments, said heterocycloaliphatic ring isselected from:

In some embodiments, two occurrences of R^(A), taken together withcarbon atoms to which they are attached, form an optionally substitutedC₆₋₁₀ aryl. In some embodiments, two occurrences of R^(A), takentogether with carbon atoms to which they are attached, form a 6 memberedaryl, optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, CN, CO₂, CF₃, OCF₃, OH, SR^(B), S(O)R^(B), SO₂R^(B),NH₂, NHR^(B), N(R^(B))₂, COOH, COOR^(B), OR^(B), or R^(B). In someembodiments, said aryl is

In some embodiments, two occurrences of R^(A), taken together withcarbon atoms to which they are attached, form an optionally substituted5-8 membered heteroaryl, having up to 4 ring members optionally andindependently replaced with nitrogen (including NH and NR^(X)), oxygen,or sulfur (including S, SO, and SO₂). In some embodiments, twooccurrences of R^(A), taken together with carbon atoms to which they areattached, form a 5 or 6 membered heteroaryl, optionally substituted with1, 2, or 3 substituents independently selected from halo, CN, CO₂, CF₃,OCF₃, OH, SR^(B), S(O)R^(B), SO₂R^(B), NH₂, NHR^(B), N(R^(B))₂, COOH,COOR^(B), OR^(B), or R^(B). In some embodiments, said heteroaryl isselected from:

In some embodiments, one R₁ is aryl or heteroaryl, each optionallysubstituted with 1, 2, or 3 of R^(A), wherein R^(A) is defined above.

In several embodiments, one R₁ is carboxy [e.g., hydroxycarbonyl oralkoxycarbonyl], amido [e.g., aminocarbonyl], amino, halo, cyano, orhydroxy.

In several embodiments, R₁ is:

-   -   wherein    -   W₁ is —C(O)—, —SO₂—, —NHC(O)—, or —CH₂—;    -   D is H, hydroxy, or an optionally substituted group selected        from aliphatic, cycloaliphatic, alkoxy, and amino; and    -   R^(A) is defined above.

In several embodiments, W₁ is —C(O)—. Or, W₁ is —SO₂—. Or, W₁ is—NHC(O)—. Or, W₁ is —CH₂—.

In several embodiments, D is OH. Or, D is an optionally substituted C₁₋₆aliphatic or an optionally substituted C₃-C₈ cycloaliphatic. Or, D is anoptionally substituted alkoxy. Or, D is an optionally substituted amino.

In several examples, D is A;

-   -   wherein each of A and B is independently H, an optionally        substituted C₁₋₆ aliphatic, an optionally substituted C₃-C₈        cycloaliphatic, an optionally substituted 3-8 membered        heterocycloaliphatic, acyl, sulfonyl, alkoxy or    -   A and B, taken together, form an optionally substituted 3-7        membered heterocycloaliphatic ring.

In some embodiments, A is H. In some embodiments, A is an optionallysubstituted C₁₋₆ aliphatic. In several examples, A is an optionallysubstituted C₁₋₆ alkyl. In one example, A is methyl. Or, A is ethyl. Or,A is n-propyl. Or, A is iso-propyl. Or, A is 2-hydroxyethyl. Or, A is2-methoxyethyl.

In several embodiments, B is C₁₋₆ straight or branched alkyl, optionallysubstituted with 1, 2, or 3 substituents each independently selectedfrom halo, oxo, CN, hydroxy, or an optionally substituted group selectedfrom alkyl, alkenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, cycloaliphatic,amino, heterocycloaliphatic, aryl, and heteroaryl. In severalembodiments, B is substituted with 1, 2, or 3 substituents eachindependently selected from halo, oxo, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,hydroxy, hydroxy-(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkyl,NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, C₃₋₈ cycloaliphatic, NH(C₃₋₈cycloaliphatic), N(C₁₋₆ alkyl)(C₃₋₈ cycloaliphatic), N(C₃₋₈cycloaliphatic)₂, 3-8 membered heterocycloaliphatic, phenyl, and 5-10membered heteroaryl. In one example, said substituent is oxo. Or, saidsubstituent is optionally substituted (C₁₋₆) alkoxy. Or, is hydroxy. Or,is NH₂. Or, is NHCH₃. Or, is NH(cyclopropyl). Or, is NH(cyclobutyl). Or,is N(CH₃)₂. Or, is CN. In one example, said substituent is optionallysubstituted phenyl. In some embodiments, B is substituted with 1, 2, or3 substituents each independently selected from an optionallysubstituted C₃₋₈ cycloaliphatic or 3-8 membered heterocycloaliphatic. Inone example, said substituent is an optionally substituted groupselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclohexenyl, morpholin-4-yl, pyrrolidin-1-yl,pyrrolidin-2-yl, 1,3-dioxolan-2-yl, and tetrahydrofuran-2-yl. In someembodiments, B is substituted with 1, 2, or 3 substituents eachindependently selected from an optionally substituted 5-8 memberedheteroaryl. In one example, said substituent is an optionallysubstituted group selected from pyridyl, pyrazyl, 1H-imidazol-1-yl, and1H-imidazol-5-yl.

In some embodiments, B is C₃-C₈ cycloaliphatic optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, oxo,alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, dialkyamino, or anoptionally substituted group selected from cycloaliphatic,heterocycloaliphatic, aryl, and heteroaryl. In several examples, B is anoptionally substituted C₃-C₈ cycloalkyl. In one embodiment, B iscyclopropyl. Or, B is cyclobutyl. Or, B is cyclopentyl. Or, B iscyclohexyl. Or, B is cycloheptyl.

In some embodiments, B is 3-8 membered heterocycloaliphatic optionallysubstituted with 1, 2, or 3 substituents independently selected fromoxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, dialkyamino, oran optionally substituted group selected from cycloaliphatic,heterocycloaliphatic, aryl, and heteroaryl. In one example, B is3-oxo-isoxazolid-4-yl.

In several embodiments, A is H and B is an optionally substituted C₁₋₆aliphatic. In several embodiments, B is substituted with 1, 2, or 3substituents. Or, both, A and B, are H. Exemplary substituents on Binclude halo, oxo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,dialkyamino, or an optionally substituted group selected fromcycloaliphatic, heterocycloaliphatic, aryl, and heteroaryl.

In several embodiments, A is H and B is an optionally substituted C₁₋₆aliphatic. Exemplary substituents include oxo, alkyl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, and an optionally substitutedheterocycloaliphatic.

In several embodiments, A and B, taken together, form an optionallysubstituted 3-7 membered heterocycloaliphatic ring. In several examples,the heterocycloaliphatic ring is optionally substituted with 1, 2, or 3substituents. Exemplary such rings include pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, oxazolidin-3-yl, and 1,4-diazepan-1-yl.Exemplary said substituents on such rings include halo, oxo, alkyl,aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl(e.g., alkylcarbonyl), amino, amido, and carboxy. In some embodiments,each of said substituents is independently halo, oxo, alkyl, aryl,heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, orcarboxy. In one embodiment, the substituent is oxo, F, Cl, methyl,ethyl, iso-propyl, 2-methoxyethyl, hydroxymethyl, methoxymethyl,aminocarbonyl, —COOH, hydroxy, acetyl, or pyridyl.

In several embodiments, R₁ is:

wherein:

-   -   W₁ is —C(O)—, —SO₂—, —NHC(O)—, or —CH₂—;    -   Each of A and B is independently H, an optionally substituted        C₁₋₆ aliphatic, an optionally substituted C₃-C₈ cycloaliphatic;        or    -   A and B, taken together, form an optionally substituted 4-7        membered heterocycloaliphatic ring.

In several examples, R₁ is selected from any one of the exemplarycompounds in Table 1.

2. Substituent R₂

Each R₂ is hydrogen, or optionally substituted C₁₋₆ aliphatic, C₃₋₆cycloaliphatic, phenyl, or heteroaryl.

In several embodiments, R₂ is a C₁₋₆ aliphatic that is optionallysubstituted with 1, 2, or 3 halo, C₁₋₂ aliphatic, or alkoxy. In severalexamples, R₂ is substituted or unsubstituted methyl, ethyl, propyl, orbutyl.

In several embodiments, R₂ is hydrogen.

3. Ring A

Ring A is an optionally substituted cycloaliphatic or an optionallysubstituted heterocycloaliphatic where the atoms of ring A adjacent toC* are carbon atoms. In several embodiments, ring A is C₃₋₇cycloaliphatic or 3-8 membered heterocycloaliphatic, each of which isoptionally substituted with 1, 2, or 3 substituents.

In several embodiments, ring A is optionally substituted with 1, 2, or 3of -Z^(B)R₇, wherein each Z^(B) is independently a bond, or anoptionally substituted branched or straight C₁₋₄ aliphatic chain whereinup to two carbon units of Z^(B) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—,—NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—,—NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or—NR^(B)SO₂NR^(B)—; each R₇ is independently R^(B), halo, —OH, —NH₂,—NO₂, —CN, or —OCF₃; and each R^(B) is independently hydrogen, anoptionally substituted C₁₋₈ aliphatic group, an optionally substitutedcycloaliphatic, an optionally substituted heterocycloaliphatic, anoptionally substituted aryl, or an optionally substituted heteroaryl.

In several embodiments, ring A is a C₃₋₇ cycloaliphatic or a 3-8membered heterocycloaliphatic, each of which is optionally substitutedwith 1, 2, or 3 substituents.

In several embodiments, ring A is a 3, 4, 5, or 6 memberedcycloaliphatic that is optionally substituted with 1, 2, or 3substituents. In several examples, ring A is an optionally substitutedcyclopropyl group. In several alternative examples, ring A is anoptionally substituted cyclobutyl group. In several other examples, ringA is an optionally substituted cyclopentyl group. In other examples,ring A is an optionally substituted cyclohexyl group. In more examples,ring A is an unsubstituted cyclopropyl.

In several embodiments, ring A is a 5, 6, or 7 membered optionallysubstitute heterocycloaliphatic. For example, ring A is an optionallysubstituted tetrahydropyranyl group.

4. Substituent R₄

Each R₄ is independently an optionally substituted aryl or heteroaryl.

In several embodiments, R₄ is an aryl having 6 to 10 members (e.g., 7 to10 members) optionally substituted with 1, 2, or 3 substituents.Examples of R₄ are optionally substituted benzene, naphthalene, orindene. Or, examples of R₄ can be optionally substituted phenyl,optionally substituted naphthyl, or optionally substituted indenyl.

In several embodiments, R₄ is an optionally substituted heteroaryl.Examples of R₄ include monocyclic and bicyclic heteroaryl, such abenzofused ring system in which the phenyl is fused with one or two C₄₋₈heterocycloaliphatic groups.

In some embodiments, R₄ is an aryl or heteroaryl, each optionallysubstituted with 1, 2, or 3 of -Z^(C)R₈. Each Z^(C) is independently abond or an optionally substituted branched or straight C₁₋₆ aliphaticchain wherein up to two carbon units of Z^(C) are optionally andindependently replaced by —CO—, —CS—, —CONR^(C)—, —CONR^(C)NR^(C)—,—CO₂—, —OCO—, —NR^(C)CO₂, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—,—NR^(C)NR^(C)—, —NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—,—NR^(C)SO₂—, or —NR^(C)SO₂NR^(C)—. Each R₈ is independently R^(C), halo,—OH, —NH₂, —NO₂, —CN, or —OCF₃. Each R^(C) is independently hydrogen, anoptionally substituted C₁₋₈ aliphatic group, an optionally substitutedcycloaliphatic, an optionally substituted heterocycloaliphatic, anoptionally substituted aryl, or an optionally substituted heteroaryl. Inone embodiment, R₄ is an aryl optionally substituted with 1, 2, or 3 ofZ^(C)R₈. In one embodiment, R₄ is an optionally substituted phenyl.

In several embodiments, R₄ is a heteroaryl optionally substituted with1, 2, or 3 substituents. Examples of R₄ include optionally substitutedbenzo[d][1,3]dioxole or 2,2-difluoro-benzo[d][1,3]dioxole.

In some embodiments, two occurrences of -Z^(C)R₈, taken together withcarbons to which they are attached, form a 4-8 membered saturated,partially saturated, or aromatic ring with up to 3 ring atomsindependently selected from the group consisting of O, NH, NR^(C), and S(including S, SO, and SO₂); wherein R^(C) is defined herein.

In several embodiments, R₄ is one selected from

C. Sub-Generic Compounds

Another aspect of the present invention includes compounds of formulaIa:

-   -   or a pharmaceutically acceptable salt thereof, wherein R₂, R₄,        and n have been defined in formula I.

Each R₁ is independently aryl, monocyclic heteroaryl or indolizinyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl,benzo[b]thiophenyl, 1H-indazolyl, benzthiazolyl, purinyl,4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl,imidazo[1,2-a]pyridinyl, or benzo[d]oxazolyl, each of which isoptionally substituted with 1, 2, or 3 of R^(A); or R₁ is independentlymethyl, trifluoromethyl, or halo. In one embodiment, R₁ is an optionallysubstituted imidazo[1,2-a]pyridine-2-yl. In one embodiment, R₁ is anoptionally substituted oxazolo[4,5-b]pyridine-2-yl. In one embodiment,R₁ is an optionally substituted 1H-pyrrolo[2,3-b]pyrid-6-yl. In oneembodiment, R₁ is an optionally substituted benzo[d]oxazol-2-yl. In oneembodiment, R₁ is an optionally substituted benzo[d]thiazol-2-yl.

In some embodiments, R₁ is a monocyclic aryl or a monocyclic heteroaryl,each is optionally substituted with 1, 2, or 3 of R^(A). In someembodiments, R₁ is substituted or unsubstituted phenyl. In oneembodiment, R₁ is substituted or unsubstituted pyrid-2-yl. In someembodiments, R₁ is pyrid-3-yl, pyrid-4-yl, thiophen-2-yl, thiophen-3-yl,1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 1H-imidazol-5-yl, 1H-pyrazol-4-yl,1H-pyrazol-3-yl, thiazol-4-yl, furan-3-yl, furan-2-yl, orpyrimidin-5-yl, each of which is optionally substituted. In someembodiments, R₁ is phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,thiophen-2-yl, thiophen-3-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl,1H-imidazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl, thiazol-4-yl,furan-3-yl, furan-2-yl, or pyrimidin-5-yl, each of which is optionallysubstituted with 1, 2, or 3 substituents independently selected from CN,or a group chosen from C₁₋₆ alkyl, carboxy, alkoxy, halo, amido,acetoamino, and aryl, each of which is further optionally substituted.

Each R^(A) is -Z^(A)R₅, wherein each Z^(A) is independently a bond or anoptionally substituted branched or straight C₁₋₆ aliphatic chain whereinup to two carbon units of Z^(A) are optionally and independentlyreplaced by —CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, NR^(B)CO₂—,NR^(B)CONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—,—SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—.

Each R₅ is independently R^(B), halo, —OH, —NH₂, —NO₂, —CN, or —OCF₃.

Each R^(B) is hydrogen, an optionally substituted C₁₋₄ aliphatic, anoptionally substituted C₃₋₆ cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted phenyl, or an optionallysubstituted heteroaryl.

Ring A is an optionally substituted cycloaliphatic, an optionallysubstituted 5 membered heterocycloaliphatic having 1, 2, or 3heteroatoms independently selected from nitrogen (including NH andNR^(X)), oxygen, or sulfur (including S, SO, and SO₂); an optionallysubstituted 6 membered heterocycloaliphatic having 1 heteroatom selectedfrom O and S (including S, SO, and SO₂); a piperidinyl optionallysubstituted with halo, aliphatic, aminocarbonyl, aminocarbonylaliphatic,aliphatic carbonyl, aliphaticsulfonyl, aryl, or combinations thereof; oran optionally substituted 7-8 membered heterocycloaliphatic having 1, 2,or 3 heteroatoms independently selected from nitrogen (including NH andNR^(X)), oxygen, or sulfur (including S, SO, and SO₂).

In some embodiments, one R₁ attached to the 3- or 4-position of thephenyl ring is an aryl or heteroaryl optionally substituted with 1, 2,or 3 of R^(A), wherein R^(A) is -Z^(A)R₅; in which each Z^(A) isindependently a bond or an optionally substituted branched or straightC₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) areoptionally and independently replaced by —CO—, —CS—, —CONR^(B)—,—CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—,—OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—,—SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—; each R₅ is independentlyR^(B), halo, —OH, —NH₂, —NO₂, —CN, or —OCF₃; and each R^(B) isindependently hydrogen, an optionally substituted C₁₋₈ aliphatic group,an optionally substituted cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, or an optionallysubstituted heteroaryl.

In some embodiments, one R₁ attached to the 3- or 4-position of thephenyl ring is a phenyl optionally substituted with 1, 2, or 3 of R^(A).

In some embodiments, one R₁ attached to the 3- or 4-position of thephenyl ring is a phenyl substituted with one of R^(A), wherein R^(A) is-Z^(A)R₅; each Z^(A) is independently a bond or an optionallysubstituted branched or straight C₁₋₆ aliphatic chain wherein up to twocarbon units of Z^(A) are optionally and independently replaced by —O—,—NHC(O)—, —C(O)NR^(B)—, —SO₂—, —NHSO₂—, —NHC(O)—, —SO—, —NR^(B)SO₂—,—SO₂NH—, —SO₂NR^(B)—, —NH—, or —C(O)O—. In one embodiment, one carbonunit of Z^(A) is replaced by —O—, —NHC(O)—, —C(O)NR^(B)—, —SO₂—,—NHSO₂—, —NHC(O)—, —SO—, —NR^(B)SO₂—, —SO₂NH—, —SO₂NR^(B)—, —NH—, or—C(O)O—. In some embodiments, R₅ is independently an optionallysubstituted aliphatic, an optionally substituted cycloaliphatic, anoptionally substituted heterocycloaliphatic, an optionally substitutedaryl, an optionally substituted heteroaryl, hydrogen, or halo.

In some embodiments, one R₁ attached to the 3- or 4-position of thephenyl ring is heteroaryl optionally substituted with 1, 2, or 3 ofR^(A). In several examples, one R₁ attached to the 3- or 4-position ofthe phenyl ring is a 5 or 6 membered heteroaryl having 1, 2, or 3heteroatoms independently selected from nitrogen (including NH andNR^(X)), oxygen or sulfur (including S, SO, and SO₂), wherein theheteroaryl is substituted with one of R^(A), wherein R^(A) is -Z^(A)R₅;wherein each Z^(A) is independently a bond or an optionally substitutedbranched or straight C₁₋₆ aliphatic chain wherein up to two carbon unitsof Z^(A) are optionally and independently replaced by —O—, —NHC(O)—,—C(O)NR^(B)—, —SO₂—, —NHSO₂—, —NHC(O)—, —SO—, —NR^(B)SO₂—, —SO₂NH—,—SO₂NR^(B)—, —NH—, or —C(O)O—. In one embodiment, one carbon unit ofZ^(A) is replaced by —O—, —NHC(O)—, —C(O)NR^(B)—, —SO₂—, —NHSO₂—,—NHC(O)—, —SO—, —NR^(B)SO₂—, —SO₂NH—, —SO₂NR^(B)—, —NH—, or —C(O)O—. Inone embodiment, R₅ is independently an optionally substituted aliphatic,an optionally substituted cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, an optionallysubstituted heteroaryl, hydrogen, or halo.

Another aspect of the present invention includes compounds of formulaIb:

-   -   or a pharmaceutically acceptable salt thereof, wherein R₂, R₄        and ring A are defined in formula I.

The R₁ attached at the para position relative to the amide is an aryl ora heteroaryl optionally substituted with 1, 2, or 3 of R^(A); whereineach R^(A) is -Z^(A)R₅, each Z^(A) is independently a bond or anoptionally substituted branched or straight C₁₋₆ aliphatic chain whereinup to two carbon units of Z^(A) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—,—NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—,—NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or—NR^(B)SO₂NR^(B)—; each R₅ is independently R^(B), halo, —OH, —NH₂,—NO₂, —CN, or —OCF₃; each R^(B) is hydrogen, an optionally substitutedC₁₋₄ aliphatic, an optionally substituted C₃₋₆ cycloaliphatic, anoptionally substituted heterocycloaliphatic, an optionally substitutedphenyl, or optionally substituted heteroaryl.

The other R₁ are each independently hydrogen, halo, optionallysubstituted C₁₋₄ aliphatic, or optionally substituted C₁₋₄ alkoxy.

In several embodiments, the R₁ attached at the para position relative tothe amide is a phenyl optionally substituted with 1, 2, or 3 of R^(A)and the other R₁'s are each hydrogen. For example, the R₁ attached atthe para position relative to the amide is phenyl optionally substitutedwith aliphatic, alkoxy, (amino)aliphatic, hydroxyaliphatic,aminosulfonyl, aminocarbonyl, alcoxycarbonyl, (aliphatic)aminocarbonyl,COOH, (aliphatic)aminosulfonyl, or combinations thereof, each of whichis optionally substituted. In other embodiments, the R₁ attached at thepara position relative to the amide is phenyl optionally substitutedwith halo. In several examples, the R₁ attached at the para positionrelative to the amide is phenyl optionally substituted with alkyl,alkoxy, (amino)alkyl, hydroxyalkyl, aminosulfonyl, (alkyl)aminocarbonyl,(alkyl)aminosulfonyl, or combinations thereof, each of which isoptionally substituted; or the R₁ attached at the para position relativeto the amide is phenyl optionally substituted with halo.

In several embodiments, the R₁ attached at the para position relative tothe amide is an optionally substituted heteroaryl. In other embodiments,the R₁ attached at the para position relative to the amide is anoptionally substituted monocyclic or optionally substituted bicyclicheteroaryl. For example, the R₁ attached at the para position relativeto the amide is a benzo[d]oxazolyl, thiazolyl, benzo[d]thiazolyl,indolyl, or imidazo[1,2-a]pyridinyl, each of which is optionallysubstituted. In other examples, the R₁ attached at the para positionrelative to the amide is a benzo[d]oxazolyl, thiazolyl,benzo[d]thiazolyl, or imidazo[1,2-a]pyridinyl, each of which isoptionally substituted with 1, 2, or 3 of halo, hydroxy, aliphatic,alkoxy, or combinations thereof, each of which is optionallysubstituted.

In several embodiments, each R₁ not attached at the para positionrelative to the amide is hydrogen. In some examples, each R₁ notattached at the para position relative to the amide is methyl, ethyl,propyl, isopropyl, or tert-butyl, each of which is optionallysubstituted with 1, 2, or 3 of halo, hydroxy, cyano, or nitro. In otherexamples, each R₁ not attached at the para position relative to theamide is halo or optionally substituted methoxy, ethoxy, or propoxy. Inseveral embodiments, each R₁ not attached at the para position relativeto the amide is hydrogen, halo, —CH₃, —OCH₃, or —CF₃.

In several embodiments, compounds of formula Ib include compounds offormulae Ib1, Ib2, Ib3, or Ib4:

-   -   where R^(A), R₁, R₂, R₄, and ring A are defined above.

In formula Ib4, ring B is monocyclic or bicyclic heteroaryl that issubstituted with 1, 2, or 3 R^(A); and “n−1” is equal to 0, 1, or 2.

In several embodiments, the R₁ attached at the para position relative tothe amide in formula Ib is an optionally substituted aryl. In severalembodiments, the R₁ attached at the para position relative to the amideis a phenyl optionally substituted with 1, 2, or 3 of R^(A). Forexample, the R₁ attached at the para position relative to the amide isphenyl optionally substituted with 1, 2, or 3 aliphatic, alkoxy, COOH,(amino)aliphatic, hydroxyaliphatic, aminosulfonyl,(aliphatic)aminocarbonyl, (aliphatic)aminosulfonyl,(((aliphatic)sulfonyl)amino)aliphatic, (heterocycloaliphatic)sulfonyl,heteroaryl, aliphaticsulfanyl, or combinations thereof, each of which isoptionally substituted; or R₁ is optionally substituted with 1-3 ofhalo.

In several embodiments, the R₁ attached at the para position relative tothe amide in formula Ib is an optionally substituted heteroaryl. Inother embodiments R₁ is an optionally substituted monocyclic or anoptionally substituted bicyclic heteroaryl. For example, R₁ is apyridinyl, thiazolyl, benzo[d]oxazolyl, or oxazolo[4,5-b]pyridinyl, eachof which is optionally substituted with 1, 2, or 3 of halo, aliphatic,alkoxy, or combinations thereof.

In several embodiments, one R₁ not attached at the para positionrelative to the amide is halo, optionally substituted C₁₋₄ aliphatic,C₁₋₄ alkoxyC₁₋₄ aliphatic, or optionally substituted C₁₋₄ alkoxy, suchas For example, one R₁ not attached at the para position relative to theamide is halo, —CH₃, ethyl, propyl, isopropyl, tert-butyl, or —OCF₃.

In several embodiments, compounds of the invention include compounds offormulae Ic1, Ic2, Ic3, Ic4, Ic5, Ic6, Ic7, or Ic8:

-   -   or pharmaceutically acceptable salts, wherein R^(A), R₂, R₁, R₄,        and ring A are defined above.

In formula Ic8, ring B is monocyclic or bicyclic heteroaryl that issubstituted with 1, 2, or 3 R^(A); and “n−1” is equal to 0, 1, or 2.

Another aspect of the present invention provides compounds of formulaId:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₄, and nare defined in formula I.

Ring A is an optionally substituted cycloaliphatic.

In several embodiments, ring A is a cyclopropyl, cyclopentyl, orcyclohexyl, each of which is optionally substituted.

Another aspect of the present invention provides compounds of formulaIe:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, and n aredefined in formula I.

R₄ is an optionally substituted phenyl or an optionally substitutedbenzo[d][1,3]dioxolyl. In several embodiments, R₄ is optionallysubstituted with 1, 2, or 3 of hydrogen, halo, optionally substitutedaliphatic, optionally substituted alkoxy, or combinations thereof. Inseveral embodiments, R₄ is phenyl that is substituted at position 2, 3,4, or combinations thereof with hydrogen, halo, optionally substitutedaliphatic, optionally substituted alkoxy, or combinations thereof. Forexample, R₄ is phenyl that is optionally substituted at the 3 positionwith optionally substituted alkoxy. In another example, R₄ is phenylthat is optionally substituted at the 3 position with —OCH₃. In anotherexample, R₄ is phenyl that is optionally substituted at the 4 positionwith halo or substituted alkoxy. A more specific example includes an R₄that is phenyl optionally substituted with chloro, fluoro, —OCH₃, or—OCF₃. In other examples, R₄ is a phenyl that is substituted at the 2position with an optionally substituted alkoxy. In more specificexamples, R₄ is a phenyl optionally substituted at the 2 position with—OCH₃. In other examples, R₄ is an unsubstituted phenyl.

In several embodiments, R₄ is optionally substitutedbenzo[d][1,3]dioxolyl. In several examples, R₄ is benzo[d][1,3]dioxolylthat is optionally mono-, di-, or tri-substituted with 1, 2, or 3 halo.In more specific examples, R₄ is benzo[d][1,3]dioxolyl that isoptionally di-substituted with halo.

Another aspect of the present invention provides compounds of formulaIf:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₄, and nare defined in formula I.

Another aspect of the present invention provides compounds of formulaIg:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₄, and nare defined in formula I.

Another aspect of the present invention provides compounds of formulaIh:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₄, and nare defined in formula I.

Ring A is an optionally substituted heterocycloaliphatic.

In several embodiments, compounds of formula Ih include compounds offormulae Ih1:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₄, and nare defined in formula I.

Another aspect of the present invention provides compounds of formulaII:

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   R₁, R₂, ring A, and R₄ are defined in formula I;    -   n is 1, 2, 3, or 4; and

Each R^(A) is independently -Z^(A)R₅, wherein each Z^(A) isindependently a bond or an optionally substituted branched or straightC₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) areoptionally and independently replaced by —CO—, —CS—, —CONR^(B)—,—CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—,—OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—,—SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—. Each R₅ is independentlyR^(B), halo, —OH, —NH₂, —NO₂, —CN, or —OCF₃. Each R^(B) is independentlyhydrogen, an optionally substituted C₁₋₈ aliphatic group, an optionallysubstituted cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, or an optionallysubstituted heteroaryl.

In some embodiments, each R₁ is an optionally substituted C₁₋₆aliphatic, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic,or an optionally substituted 3 to 10 membered heterocycloaliphatic, eachof which is optionally substituted with 1, 2, or 3 of R^(A); whereineach R^(A) is -Z^(A)R₅, wherein each Z^(A) is independently a bond or anoptionally substituted branched or straight C₁₋₆ aliphatic chain whereinup to two carbon units of Z^(A) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—,—NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—,—NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or—NR^(B)SO₂NR^(B)—; and R₅ is independently R^(B), halo, —OH, —NH₂, —NO₂,—CN, or —OCF₃; wherein each R^(B) is independently hydrogen, anoptionally substituted C₁₋₈ aliphatic group, an optionally substitutedcycloaliphatic, an optionally substituted heterocycloaliphatic, anoptionally substituted aryl, or an optionally substituted heteroaryl.

In some embodiments, R₂ is C₁₋₄ aliphatic, C₃₋₆ cycloaliphatic, phenyl,or heteroaryl, each of which is optionally substituted, or R₂ ishydrogen.

In some embodiments, ring A is an optionally substituted C₃₋₇cycloaliphatic or an optionally substituted C₃₋₇ heterocycloaliphaticwhere the atoms of ring A adjacent to C* are carbon atoms, and said ringA is optionally substituted with 1, 2, or 3 of -Z^(B)R₇, wherein eachZ^(B) is independently a bond, or an optionally substituted branched orstraight C₁₋₄ aliphatic chain wherein up to two carbon units of Z^(B)are optionally and independently replaced by —CO—, —CS—, —CONR^(B)—,—CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—,—OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—,—SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—; Each R₇ is independentlyR^(B), halo, —OH, —NH₂, —NO₂, —CN, or —OCF₃.

In some embodiments, each R⁴ is an aryl or heteroaryl, each of which isoptionally substituted with 1, 2, or 3 of -Z^(C)R₈, wherein each Z^(C)is independently a bond or an optionally substituted branched orstraight C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(C)are optionally and independently replaced by —CO—, —CS—, —CONR^(C)—,—CONR^(C)NR^(C)—, —CO₂—, —OCO—, —NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—,—OCONR^(C)—, —NR^(C)NR^(C)—, —NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—,—SO₂NR^(C)—, —NR^(C)SO₂—, or —NR^(C)SO₂NR^(C)—; wherein each R₈ isindependently R^(C), halo, —OH, —NH₂, —NO₂, —CN, or —OCF₃; wherein eachR^(C) is independently an optionally substituted C₁₋₈ aliphatic group,an optionally substituted cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, or an optionallysubstituted heteroaryl.

Another aspect of the present invention provides compounds of formulaIIa:

or pharmaceutically acceptable salts thereof, wherein R₂, ring A and R₄are defined in formula I, and R^(A) is defined above.

Another aspect of the present invention provides compounds of formulaIIb:

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₄, and nare defined in formula I and R^(A) is defined in formula II.

Another aspect of the present invention provides compounds of formulaIIc:

or a pharmaceutically acceptable salt thereof,wherein:

T is an optionally substituted C₁₋₂ aliphatic chain, wherein each of thecarbon units is optionally and independently replaced by —CO—, —CS—,—COCO—, —SO₂—, —B(OH)—, or —B(O(C₁₋₆ alkyl))-;

Each of R₁ is independently an optionally substituted C₁₋₆ aliphatic, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted 3 to 10 membered cycloaliphatic, an optionallysubstituted 3 to 10 membered heterocycloaliphatic, carboxy, amido,amino, halo, or hydroxy;

Each R^(A) is independently -Z^(A)R₅, wherein each Z^(A) isindependently a bond or an optionally substituted branched or straightC₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) areoptionally and independently replaced by —CO—, —CS—, —CONR^(B)—,—CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—,—OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—,—SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—;

Each R₅ is independently R^(B), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or—OCF₃;

-   -   or two R^(A), taken together with atoms to which they are        attached, form a 3-8 membered saturated, partially unsaturated,        or aromatic ring with up to 3 ring members independently        selected from the group consisting of O, NH, NR^(B), and S,        provided that one R^(A) is attached to carbon 3″ or 4″;    -   Each R^(B) is independently hydrogen, an optionally substituted        C₁₋₈ aliphatic group, an optionally substituted cycloaliphatic,        an optionally substituted heterocycloaliphatic, an optionally        substituted aryl, or an optionally substituted heteroaryl; and    -   n is 2 or 3 provided that when n is 3, a first R₁ is attached        ortho relative to the phenyl ring substituted with R^(A) and        that a second one R₁ is attached para relative to the phenyl        ring substituted with R^(A).

In some embodiments, T is an optionally substituted —CH₂—. In some otherembodiments, T is an optionally substituted —CH2CH₂—.

In some embodiments, T is optionally substituted by -Z^(F)R¹⁰; whereineach Z^(F) is independently a bond or an optionally substituted branchedor straight C₁₋₆ aliphatic chain wherein up to two carbon units of Z^(F)are optionally and independently replaced by —CO—, —CS—, —CONR^(F)—,—CONR^(F)NR^(F)—, —CO₂—, —OCO—, —NR^(F)CO₂—, —O—, —NR^(F)CONR^(F)—,—OCONR^(F)—, —NR^(F)NR^(F)—, —NR^(F)CO—, —S—, —SO—, —SO₂—, —NR^(F)—,—SO₂NR^(F)—, —NR^(F)SO₂—, or —NR^(F)SO₂NR^(F)—; R¹⁰ is independentlyR^(F), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; each R^(F) isindependently hydrogen, an optionally substituted C₁₋₈ aliphatic group,an optionally substituted cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, or an optionallysubstituted heteroaryl. In one example, Z^(F) is —O—.

In some embodiments, R₁₀ is an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, an optionally substituted C₃₋₇cycloaliphatic, or an optionally substituted C₆₋₁₀ aryl. In oneembodiment, R₁₀ is methyl, ethyl, iso-propyl, or tert-butyl.

In some embodiments, up to two carbon units of T are independently andoptionally replaced with —CO—, —CS—, —B(OH)—, or —B(O(C₁₋₆ alkyl)-.

In some embodiments, T is selected from the group consisting of —CH₂—,—CH₂CH₂—, —CF₂—, —C(CH₃)₂—, —C(O)—,

—C(Phenyl)₂-, —B(OH)—, and —CH(OEt)-. In some embodiments, T is —CH₂—,—CF₂—, —C(CH₃)₂—,

or —C(Phenyl)₂-. In other embodiments, T is —CH₂H₂—, —C(O)—, —B(OH)—,and —CH(OEt)-. In several embodiments, T is —CH₂—, —CF₂—, —C(CH₃)₂—,

More preferably, T is —CH₂—, —CF₂—, or —C(CH₃)₂—. In severalembodiments, T is —CH₂—. Or, T is —CF₂—. Or, T is —C(CH₃)₂—. Or, T is

In some embodiments, each R₁ is hydrogen. In some embodiments, each ofR₁ is independently -Z^(E)R₉, wherein each Z^(E) is independently a bondor an optionally substituted branched or straight C₁₋₆ aliphatic chainwherein up to two carbon units of Z^(E) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(E), —CONR^(E)NR^(E)—, —CO₂—, —OCO—,—NR^(E)CO₂—, —O—, —NR^(E)CONR^(E)—, —OCONR^(E)—, —NR^(E)NR^(E)—,—NR^(E)CO—, —S—, —SO—, —SO₂—, —NR^(E)—, —SO₂NR^(E), —NR^(E)SO₂—, or—NR^(E)SO₂NR^(E)—. Each R₉ is independently H, R^(E), halo, —OH, —NH₂,—NO₂, —CN, —CF₃, or —OCF₃. Each R^(E) is independently an optionallysubstituted group selected from C₁₋₈ aliphatic group, cycloaliphatic,heterocycloaliphatic, aryl, and heteroaryl.

In several embodiments, a first R₁ is attached ortho relative to thephenyl ring substituted with R^(A) is H, F, Cl, CF₃, OCH₃, —OCF₃,methyl, ethyl, iso-propyl, or tert-butyl.

In several embodiments, a first R₁ is attached ortho relative to thephenyl ring substituted with R^(A) is -Z^(E)R₉, wherein each Z^(E) isindependently a bond or an optionally substituted branched or straightC₁₋₆ aliphatic chain wherein up to two carbon units of Z^(E) areoptionally and independently replaced by —CO—, —CONR^(E)—, —CO₂—, —O—,—S—, —SO—, —SO₂—, —NR^(E)—, or —SO₂NR^(E)—. Each R₉ is hydrogen, R^(E),halo, —OH, —NH₂, —CN, —CF₃, or —OCF₃. Each R^(E) is independently anoptionally substituted group selected from the group including C₁₋₈aliphatic group, a cycloaliphatic, a heterocycloaliphatic, an aryl, anda heteroaryl. In one embodiment, Z^(E) is a bond. In one embodiment,Z^(E) is a straight C₁₋₆ aliphatic chain, wherein one carbon unit ofZ^(E) is optionally replaced by —CO—, —CONR^(E), —CO₂—, —O—, or—NR^(E)—. In one embodiment, Z^(E) is a C₁₋₆ alkyl chain. In oneembodiment, Z^(E) is —CH₂—. In one embodiment, Z^(E) is CO—. In oneembodiment, Z^(E) is —CO₂—. In one embodiment, Z^(E) is —CONR^(E). Inone embodiment, Z^(E) is —CO—.

In some embodiments, R₉ is H, —NH₂, hydroxy, —CN, or an optionallysubstituted group selected from the group of C₁₋₈ aliphatic, C₃₋₈cycloaliphatic, 3-8 membered heterocycloaliphatic, C₆₋₁₀ aryl, and 5-10membered heteroaryl. In one embodiment, R₉ is H. In one embodiment, R₉is hydroxy. Or, R₉ is —NH₂. Or, R₉ is —CN. In some embodiments, R₉ is anoptionally substituted 3-8 membered heterocycloaliphatic, having 1, 2,or 3 ring members independently selected from nitrogen (including NH andNR^(X)), oxygen, and sulfur (including S, SO, and SO₂). In oneembodiment, R₉ is an optionally substituted five memberedheterocycloaliphatic with one nitrogen (including NH and NR^(X)) ringmember. In one embodiment, R₉ is an optionally substitutedpyrrolidin-1-yl. Examples of said optionally substituted pyrrolidin-1-ylinclude pyrrolidin-1-yl and 3-hydroxy-pyrrolidin-1-yl. In oneembodiment, R₉ is an optionally substituted six memberedheterocycloaliphatic with two heteroatoms independently selected fromnitrogen (including NH and NR^(X)) and oxygen. In one embodiment, R₉ ismorpholin-4-yl. In some embodiments, R₉ is an optionally substituted5-10 membered heteroaryl. In one embodiment, R₉ is an optionallysubstituted 5 membered heteroaryl, having 1, 2, 3, or 4 ring membersindependently selected from nitrogen (including NH and NR^(X)), oxygen,and sulfur (including S, SO, and SO₂). In one embodiment, R₉ is1H-tetrazol-5-yl.

In one embodiment, a first R₁ is attached ortho relative to the phenylring substituted with R^(A) is Z^(E)R₉; wherein Z^(E) is CH₂ and R₉ is1H-tetrazol-5-yl. In one embodiment, one R₁′ is Z^(E)R₉; wherein Z^(E)is CH₂ and R₉ is morpholin-4-yl. In one embodiment, one R₁′ is Z^(E)R₉;wherein Z^(E) is CH₂ and R₉ is pyrrolidin-1-yl. In one embodiment, oneR₁′ is Z^(E)R₉; wherein Z^(E) is CH₂ and R₉ is3-hydroxy-pyrrolidin-1-yl. In one embodiment, one R₁′ is Z^(E)R₉;wherein Z^(E) is CO and R₉ is 3-hydroxy-pyrrolidin-1-yl.

In some embodiments, a first R₁ is attached ortho relative to the phenylring substituted with R^(A) is selected from CH₂OH, COOH, CH₂OCH₃,COOCH₃, CH₂NH₂, CH₂NHCH₃, CH₂CN, CONHCH₃, CH₂CONH₂, CH₂OCH₂CH₃,CH₂N(CH₃)₂, CON(CH₃)₂, CH₂NHCH₂CH₂OH, CH₂NHCH₂CH₂COOH, CH₂OCH(CH₃)₂,CONHCH(CH₃)CH₂OH, or CONHCH(tert-butyl)CH₂OH.

In some embodiments, a first R₁ is attached ortho relative to the phenylring substituted with R^(A) is an optionally substituted C₃₋₁₀cycloaliphatic or an optionally substituted 4-10 memberedheterocycloaliphatic. In one embodiment, R₁′ is an optionallysubstituted 4, 5, or 6 membered heterocycloalkyl containing one oxygenatom. In one embodiment, R₁′ is 3-methyloxetan-3-yl.

In some embodiments, a second one R₁ is attached para relative to thephenyl ring substituted with R^(A) is selected from the group consistingof H, halo, optionally substituted C₁₋₆ aliphatic, and optionallysubstituted —O(C₁₋₆ aliphatic). In some embodiments, a second one R₁ isattached para relative to the phenyl ring substituted with R^(A) isselected from the group consisting of H, methyl, ethyl, iso-propyl,tert-butyl, F, Cl, CF₃, —OCH₃, —OCH₂CH₃, —O-(iso-propyl),—O-(tert-butyl), and —OCF₃. In one embodiment, a second one R₁ isattached para relative to the phenyl ring substituted with R^(A) is H.In one embodiment, a second one R₁ is attached para relative to thephenyl ring substituted with R^(A) is methyl. In one embodiment, asecond one R₁ is attached para relative to the phenyl ring substitutedwith R^(A) is F. In one embodiment, a second one R₁ is attached pararelative to the phenyl ring substituted with R^(A) is —OCF₃. In oneembodiment, a second one R₁ is attached para relative to the phenyl ringsubstituted with R^(A) is —OCH₃.

In some embodiments, one R^(A) is attached to carbon 3″ or 4″ and is-Z^(A)R₅, wherein each Z^(A) is independently a bond or an optionallysubstituted branched or straight C₁₋₆ aliphatic chain wherein up to twocarbon units of Z^(A) are optionally and independently replaced by —CO—,—CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—,—NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—,—SO₂—, —NR^(B)—, —SO₂NR^(B)—, NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—. In yetsome embodiments, Z^(A) is independently a bond or an optionallysubstituted branched or straight C₁₋₆ aliphatic chain wherein one carbonunit of Z^(A) is optionally replaced by —CO—, —SO—, —SO₂—, —COO—, —OCO—,—CONR^(B)—, —NR^(B)CO—, —NR^(B)CO₂—, —O—, —NR^(B)SO₂—, or —SO₂NR^(B)—.In some embodiments, one carbon unit of Z^(A) is optionally replaced by—CO—. Or, by —SO—. Or, by —SO₂—. Or, by —COO—. Or, by —OCO—. Or, by—CONR^(B)—. Or, by —NR^(B)CO—. Or, by —NR^(B)CO₂—. Or, by —O—. Or, by—NR^(B)SO₂—. Or, by —SO₂NR^(B)—.

In several embodiments, R₅ is hydrogen, halo, —OH, —NH₂, —CN, —CF₃,—OCF₃, or an optionally substituted group selected from the groupconsisting of C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, 3-8 memberedheterocycloaliphatic, C₆₋₁₀ aryl, and 5-10 membered heteroaryl. Inseveral examples, R₅ is hydrogen, F, Cl, —OH, —CN, —CF₃, or —OCF₃. Insome embodiments, R₅ is C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, 3-8membered heterocycloaliphatic, C₆₋₁₀ aryl, and 5-10 membered heteroaryl,each of which is optionally substituted with 1 or 2 substituentsindependently selected from the group consisting of R^(B), oxo, halo,—OH, —NR^(B)R^(B), —OR^(B), —COOR^(B), and —CONR^(B)R^(B). In severalexamples, R₅ is optionally substituted by 1 or 2 substituentsindependently selected from the group consisting of oxo, F, Cl, methyl,ethyl, iso-propyl, tert-butyl, —CH₂OH, —CH₂CH₂OH, —C(O)OH, —C(O)NH₂,—CH₂O(C₁₋₆ alkyl), —CH₂CH₂O(C₁₋₆ alkyl), and —C(O)(C₁₋₆ alkyl).

In one embodiment, R₅ is hydrogen. In some embodiments, R₅ is selectedfrom the group consisting of straight or branched C₁₋₆ alkyl or straightor branched C₂₋₆ alkenyl; wherein said alkyl or alkenyl is optionallysubstituted with 1 or 2 substituents independently selected from thegroup consisting of R^(B), oxo, halo, —OH, —NR^(B)R^(B), —OR^(B),—COOR^(B), and —CONR^(B)R^(B).

In other embodiments, R₅ is C₃₋₈ cycloaliphatic optionally substitutedwith 1 or 2 substituents independently selected from the groupconsisting of R^(B), oxo, halo, —OH, —NR^(B)R^(B), —OR^(B), —COOR^(B),and —CONR^(B)R^(B). Examples of cycloaliphatic include but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

In yet other embodiments, R₅ is a 3-8 membered heterocyclic with 1 or 2heteroatoms independently selected from the group consisting of nitrogen(including NH and NR^(X)), oxygen, and sulfur (including S, SO, andSO₂); wherein said heterocyclic is optionally substituted with 1 or 2substituents independently selected from the group R^(B), oxo, halo,—OH, —NR^(B)R^(B), —OR^(B), —COOR^(B), and —CONR^(B)R^(B). Examples of3-8 membered heterocyclic include but are not limited to

In yet some other embodiments, R₅ is an optionally substituted 5-8membered heteroaryl with one or two ring atom independently selectedfrom the group consisting of nitrogen (including NH and NR^(X)), oxygen,and sulfur (including S, SO, and SO₂). Examples of 5-8 memberedheteroaryl include but are not limited to

In some embodiments, two R^(A)s, taken together with carbons to whichthey are attached, form an optionally substituted 4-8 memberedsaturated, partially unsaturated, or aromatic ring with 0-2 ring atomsindependently selected from the group consisting of nitrogen (includingNH and NR^(X)), oxygen, and sulfur (including S, SO, and SO₂). Examplesof two RAS, taken together with phenyl containing carbon atoms to whichthey are attached, include but are not limited to

In some embodiments, one R^(A) not attached top the carbon 3″ or 4″ isselected from the group consisting of H, R^(B), halo, —OH,—(CH₂)_(r)NR^(B)R^(B), —(CH₂)_(r)—OR^(B), —SO₂—R^(B), NR^(B)—SO₂—R^(B),—SO₂NR^(B)R^(B), —C(O)R^(B), —C(O)OR^(B), —OC(O)OR^(B),—NR^(B)C(O)OR^(B), and —C(O)NR^(B)R^(B); wherein r is 0, 1, or 2; andeach R^(B) is independently hydrogen, an optionally substituted C₁₋₈aliphatic group, an optionally substituted cycloaliphatic, an optionallysubstituted heterocycloaliphatic, an optionally substituted aryl, or anoptionally substituted heteroaryl. In other embodiments, one R^(A) notattached top the carbon 3″ or 4″ is selected from the group consistingof H, C₁₋₆ aliphatic, halo, —CN, —NH₂, —NH(C₁₋₆ aliphatic), —N(C₁₋₆aliphatic)₂, —CH₂—N(C₁₋₆ aliphatic)₂, —CH₂—NH(C₁₋₆ aliphatic), —CH₂NH₂,—OH, —O(C₁₋₆ aliphatic), —CH₂OH, —CH₂—O(C₁₋₆ aliphatic), —SO₂(C₁₋₆aliphatic), —N(C₁₋₆ aliphatic)-SO₂(C₁₋₆ aliphatic), —NH—SO₂(C₁₋₆aliphatic), —SO₂NH₂, —SO₂NH(C₁₋₆ aliphatic), —SO₂N(C₁₋₆ aliphatic)₂,—C(O)(C₁₋₆ aliphatic), —C(O)O(C₁₋₆ aliphatic), —C(O)OH, —OC(O)O(C₁₋₆aliphatic), —NHC(O)(C₁₋₆ aliphatic), —NHC(O)O(C₁₋₆ aliphatic), —N(C₁₋₆aliphatic)C(O)O(C₁₋₆ aliphatic), —C(O)NH₂, and —C(O)N(C₁₋₆ aliphatic)₂.In several examples, R^(A2) is selected from the group consisting of H,C₁₋₆ aliphatic, halo, —CN, —NH₂, —CH₂NH₂, —OH, —O(C₁₋₆ aliphatic),—CH₂OH, —SO₂(C₁₋₆ aliphatic), —NH—SO₂(C₁₋₆ aliphatic), —C(O)O(C₁₋₆aliphatic), —C(O)OH, —NHC(O)(C₁₋₆ aliphatic), —C(O)NH₂, —C(O)NH(C₁₋₆aliphatic), and —C(O)N(C₁₋₆ aliphatic)₂. For examples, one R^(A) notattached top the carbon 3″ or 4″ is selected from the group consistingof H, methyl, ethyl, n-propyl, iso-propyl, tert-butyl, F, Cl, CN, —NH₂,—CH₂NH₂, —OH, —OCH₃, —O-ethyl, —O-(iso-propyl), —O-(n-propyl), —CH₂OH,—SO₂CH₃, —NH—SO₂CH₃, —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OH, —NHC(O)CH₃,—C(O)NH₂, and —C(O)N(CH₃)₂. In one embodiment, all R^(A)s not attachedtop the carbon 3″ or 4″ are hydrogen. In another embodiment, one R^(A)not attached top the carbon 3″ or 4″ is methyl. Or, one R^(A) notattached top the carbon 3″ or 4″ is ethyl. Or, one R^(A) not attachedtop the carbon 3″ or 4″ is F. Or, one R^(A) not attached top the carbon3″ or 4″ is Cl. Or, one R^(A) not attached top the carbon 3″ or 4″ is—OCH₃.

In one embodiment, the present invention provides compounds of formulaIId or formula IIe:

-   -   wherein T, each R^(A), and R₁ are as defined above.

In one embodiment, T is —CH₂—, —CF₂—, —C(CH₃)₂—, or

In one embodiment, T is —CH₂—. In one embodiment, T is —CF₂—. In oneembodiment, T is —C(CH₃)₂—. In one embodiment, T is

In one embodiment, R₁ is selected from the group consisting of H, halo,CF₃, or an optionally substituted group selected from C₁₋₆ aliphatic,—O(C₁₋₆ aliphatic), C₃₋₅ cycloalkyl, 3-6 membered heterocycloalkylcontaining one oxygen atom, carboxy, and aminocarbonyl. Said C₁₋₆aliphatic, —O(C₁₋₆ aliphatic), C₃₋₅ cycloalkyl, 3-6 memberedheterocycloalkyl containing one oxygen atom, carboxy, or aminocarbonylis optionally substituted with halo, CN, hydroxy, or a group selectedfrom amino, branched or straight C₁₋₆ aliphatic, branched or straightalkoxy, aminocarbonyl, C₃₋₈ cycloaliphatic, 3-10 memberedheterocyclicaliphatic having 1, 2, or 3 ring membered independentlyselected from nitrogen (including NH and NR^(X)), oxygen, or sulfur(including S, SO, and SO₂), C₆₋₁₀ aryl, and 5-10 membered heteroaryl,each of which is further optionally substituted with halo or hydroxy.Exemplary embodiments include H, methyl, ethyl, iso-propyl, tert-butyl,F, Cl, CF₃, CHF₂, —OCF₃, —OCH₃, —OCH₂CH₃, —O-(iso-propyl),—O-(tert-butyl), —COOH, —COOCH₃, —CONHCH(tert-butyl)CH₂OH,—CONHCH(CH₃)CH₂OH, —CON(CH₃)₂, —CONHCH₃, —CH₂CONH₂,pyrrolid-1-yl-methyl, 3-hydroxy-pyrrolid-1-yl-methyl,morpholin-4-yl-methyl, 3-hydroxy-pyrrolid-1-yl-formyl,tetrazol-5-yl-methyl, cyclopropyl, hydroxymethyl, methoxymethyl,ethoxymethyl, methylaminomethyl, dimethylaminomethyl, cyanomethyl,2-hydroxyethylaminomethyl, iso-propoxymethyl, or 3-methyloxetan-3-yl. INstill other embodiments, R₁ is H. Or, R₁ is methyl. Or, R₁ is ethyl. Or,R₁ is CF₃. Or, R₁ is oxetanyl.

In some embodiments, R^(A) attached at the carbon 3″ or 4″ is H, halo,OH, CF₃, OCF₃, CN, SCH₃, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, amino, alkoxy, or 3-8 membered heterocycloaliphatichaving 1, 2, or 3 ring members each independently chosen from nitrogen(including NH and NR^(X)), oxygen, or sulfur (including S, SO, and SO₂).In some embodiments, R^(A) attached at the carbon 3″ or 4″ is H, F, Cl,OH, CF₃, OCF₃, CN, or SCH₃. In some embodiments, R^(A) attached at thecarbon 3″ or 4″ is C₁₋₆ alkyl, amino, alkoxy, or 3-8 memberedheterocycloalkyl having 1, 2, or 3 ring members each independentlychosen from nitrogen (including NH and NR^(X)), oxygen, or sulfur(including S, SO, and SO₂); wherein said alkyl, amino, alkoxy, orheterocycloalkyl each is optionally substituted with 1, 2, or 3 groupsindependently selected from oxo, halo, hydroxy, or an optionallysubstituted group selected from C₁₋₆ aliphatic, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, carbonyl, amino, and carboxy. Inone embodiment, R^(A) attached at the carbon 3″ or 4″ is H, F, Cl, OH,CF₃, OCF₃, CN, SCH₃, methyl, ethyl, iso-propyl, tert-butyl,2-methylpropyl, cyanomethyl, aminomethyl, hydroxymethyl, 1-hydroxyethyl,methoxymethyl, methylaminomethyl, (2′-methylpropylamino)-methyl,1-methyl-1-cyanoethyl, n-propylaminomethyl, dimethylaminomethyl,2-(methylsulfonyl)-ethyl, CH₂COOH, CH(OH)COOH, diethylamino,piperid-1-yl, 3-methyloxetan-3-yl, 2,5-dioxopyrrolid-1-yl,morpholin-4-yl, 2-oxopyrrolid-1-yl, tetrazol-5-yl, methoxy, ethoxy,OCH₂COOH, amino, dimethylamino, NHCH₂COOH, or acetyl.

In one embodiment, R^(A) attached at the carbon 3″ or 4″ is Z^(A)R₅,wherein Z^(A) is selected from CONH, CON(C₁₋₆ alkyl), NHCO, SO₂NH,SO₂N(C₁₋₆ alkyl), NHSO₂, CH₂NHSO₂, CH₂N(CH₃)SO₂, CH₂NHCO, CH₂N(CH₃)CO,COO, SO₂, SO, or CO. In one embodiment, R^(A) attached at the carbon 3″or 4″ is Z^(A)R₅, wherein Z^(A) is selected from CONH, SO₂NH, SO₂N(C₁₋₆alkyl), CH₂NHSO₂, CH₂N(CH₃)SO₂, CH₂NHCO, COO, SO₂, or Co.

In one embodiment, Z^(A) is COO and R₅ is H. In one embodiment, Z^(A) isCOO and R₅ is an optionally substituted straight or branched C₁₋₆aliphatic. In one embodiment, Z^(A) is COO and R₅ is an optionallysubstituted straight or branched C₁₋₆ alkyl. In one embodiment, Z^(A) isCOO and R₅ is C₁₋₆ alkyl. In one embodiment, Z^(A) is COO and R₅ ismethyl.

In one embodiment, Z^(A) is CONH and R₅ is H. In one embodiment, Z^(A)is CONH and R₅ is an optionally substituted straight or branched C₁₋₆aliphatic. In one embodiment, Z^(A) is CONH and R₅ is C₁₋₆ straight orbranched alkyl optionally substituted with one or more groupsindependently selected from —OH, halo, CN, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloaliphatic, optionallysubstituted 3-8 membered heterocycloaliphatic, optionally substitutedC₆₋₁₀ aryl, optionally substituted 5-8 membered heteroaryl, optionallysubstituted alkoxy, optionally substituted amino, and optionallysubstituted aminocarbonyl. In one embodiment, Z^(A) is CONH and R₅ is2-(dimethylamino)ethyl, cyclopropylmethyl, cyclohexylmethyl,2-(cyclohexen-1-yl)ethyl, 3-(morpholin-4-yl)propyl,2-(morpholin-4-yl)ethyl, 2-(1H-imidazol-4-yl)ethyl,tetrahydrofuran-2-yl-methyl, 2-(pyrid-2-yl)ethyl,(1-ethyl-pyrrolidin-2-yl)methyl, 1-hydroxymethylpropyl,1-hydroxymethylbutyl, 1-hydroxymethylpentyl,1-hydroxymethyl-2-hydroxyethyl, 1-hydroxymethyl-2-methylpropyl,1-hydroxymethyl-3-methyl-butyl, 2,2-dimethyl-1-hydroxymethyl-propyl,1,1-di(hydroxymethyl)ethyl, 1,1-di(hydroxymethyl)propyl, 3-ethoxypropyl,2-acetoaminoethyl, 2-(2′-hydroxyethoxy)ethyl, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,2-hydroxy-1-methylethyl, 2-methoxyethyl, 3-methoxypropyl, 2-cyanoethyl,or aminoformylmethyl. In one embodiment, Z^(A) is CONH and R₅ isstraight or branched C₁₋₆ alkyl. In one embodiment, Z^(A) is CONH and R₅is methyl, ethyl, n-propyl, iso-propyl, 3-methylbutyl,3,3-dimethylbutyl, 2-methylpropyl, or tert-butyl.

In one embodiment, Z^(A) is CONH and R₅ is an optionally substitutedC₃₋₁₀ cycloaliphatic. In one embodiment, Z^(A) is CONH and R₅ is anoptionally substituted C₃₋₁₀ cycloalkyl. In one embodiment, Z^(A) isCONH and R₅ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiment, Z^(A) is CONH and R₅ is an optionally substituted3-8 membered heterocycloaliphatic. In several examples, Z^(A) is CONHand R₅ is an optionally substituted 3-8 membered heterocycloalkyl,having 1, 2, or 3 ring members independently selected from nitrogen(including NH and NR^(X)), oxygen, or sulfur (including S, SO, and SO₂).In several examples, Z^(A) is CONH and R₅ is 3-8 memberedheterocycloalkyl optionally substituted with 1, 2, or 3 groupsindependently selected from oxo, halo, hydroxy, or an optionallysubstituted group selected from C₁₋₆ aliphatic, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, carbonyl, amino, and carboxy. Inone embodiment, Z^(A) is CONH and R₅ is 3-oxo-isoxazolidin-4-yl.

In some embodiments, Z^(A) is CON(C₁₋₆ aliphatic) and R₅ is anoptionally substituted C₁₋₆ aliphatic or an optionally substituted C₃₋₈cycloaliphatic. In some embodiments, Z^(A) is CON (branched or straightC₁₋₆ alkyl) and R₅ is branched or straight C₁₋₆ alkyl or C₃₋₈cycloaliphatic, each optionally substituted with 1, 2, or 3 groupsindependently selected from CN, OH, and an optionally substituted groupchosen from amino, branched or straight C₁₋₆ aliphatic, C₃₋₈cycloaliphatic, 3-8 membered heterocycloaliphatic, C₆₋₁₀ aryl, and 5-10membered heteroaryl. In one embodiment, Z^(A) is CON(CH₃) and R₅ ismethyl, ethyl, n-propyl, butyl, 2-pyrid-2-ylethyl, dimethylaminomethyl,2-dimethylaminoethyl, 1,3-dioxolan-2-ylmethyl, 2-cyanoethyl,cyanomethyl, or 2-hydroxyethyl. In one embodiment, Z^(A) is CON(CH₂CH₃)and R₅ is ethyl, propyl, iso-propyl, n-butyl, tert-butyl, cyclohexyl,2-dimethylaminoethyl, or 2-hydroxyethyl. In one embodiment, Z^(A) isCON(CH₂CH₂CH₃) and R₅ is cyclopropylmethyl or 2-hydroxyethyl. In oneembodiment, Z^(A) is CON(iso-propyl) and R₅ is iso-propyl.

In some embodiments, Z^(A) is CH₂NHCO and R₅ is an optionallysubstituted straight or branched C₁₋₆ aliphatic, an optionallysubstituted C₃₋₈ cycloaliphatic, an optionally substituted alkoxy, or anoptionally substituted heteroaryl. In some embodiments, Z^(A) is CH₂NHCOand R₅ is straight or branched C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or alkoxy,each of which is optionally substituted with 1, 2, or 3 groupsindependently selected from halo, oxo, hydroxy, or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, 3-8membered heterocycloaliphatic, C₆₋₁₀ aryl, 5-10 membered heteroaryl,alkoxy, amino, carboxyl, and carbonyl. In one embodiment, Z^(A) isCH₂NHCO and R₅ is methyl, ethyl, 1-ethylpropyl, 2-methylpropyl,1-methylpropyl, 2,2-dimethylpropyl, n-propyl, iso-propyl, n-butyl,tert-butyl, cyclopentyl, dimethylaminomethyl, methoxymethyl,(2′-methoxyethoxy)methyl, (2′-methoxy)ethoxy, methoxy, ethoxy,iso-propoxy, or tert-butoxy. In one embodiment, Z^(A) is CH₂NHCO and R₅is an optionally substituted heteroaryl. In one embodiment, Z^(A) isCH₂NHCO and R₅ is pyrazinyl.

In some embodiments, Z^(A) is CH₂N(CH₃)CO and R₅ is an optionallysubstituted straight or branched C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, oran optionally substituted heteroaryl. In some embodiments, Z^(A) isCH₂N(CH₃)CO and R₅ is straight or branched C₁₋₆ alkyl, or 5 or 6membered heteroaryl, each of which is optionally substituted with 1, 2,or 3 groups independently selected from halo, oxo, hydroxy, or anoptionally substituted group selected from C₁₋₆ aliphatic, C₃₋₈cycloaliphatic, 3-8 membered heterocycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, alkoxy, amino, carboxyl, and carbonyl. In oneembodiment, Z^(A) is CH₂N(CH₃)CO and R₅ is methoxymethyl,(2′-methoxyethoxy)methyl, dimethylaminomethyl, or pyrazinyl. In someembodiments, Z^(A) is CH₂N(CH₃)CO and R₅ is branched or straight C₁₋₆alkyl or C₃₋₈ cycloalkyl. In one embodiment, Z^(A) is CH₂N(CH₃)CO and R₅is methyl, ethyl, iso-propyl, n-propyl, n-butyl, tert-butyl,1-ethylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, or cyclopentyl.

In one embodiment, Z^(A) is SO₂NH and R₅ is H. In some embodiments,Z^(A) is SO₂NH and R₅ is an optionally substituted straight or branchedC₁₋₆ aliphatic. In some embodiments, Z^(A) is SO₂NH and R₅ is straightor branched C₁₋₆ alkyl optionally substituted with halo, oxo, hydroxy,or an optionally substituted group selected from C₁₋₆ aliphatic, C₃₋₈cycloaliphatic, 3-8 membered heterocycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, alkoxy, amino, amido, carboxyl, or carbonyl. In oneembodiment, Z^(A) is SO₂NH and R₅ is methyl. In one embodiment, Z^(A) isSO₂NH and R₅ is ethyl. In one embodiment, Z^(A) is SO₂NH and R₅ isn-propyl. In one embodiment, Z^(A) is SO₂NH and R₅ is iso-propyl. In oneembodiment, Z^(A) is SO₂NH and R₅ is tert-butyl. In one embodiment,Z^(A) is SO₂NH and R₅ is 3,3-dimethylbutyl. In one embodiment, Z^(A) isSO₂NH and R₅ is CH₂CH₂OH. In one embodiment, Z^(A) is SO₂NH and R₅ isCH₂CH₂OCH₃. In one embodiment, Z^(A) is SO₂NH and R₅ is CH(CH₃)CH₂OH. Inone embodiment, Z^(A) is SO₂NH and R₅ is CH₂CH(CH₃)OH. In oneembodiment, Z^(A) is SO₂NH and R₅ is CH(CH₂OH)₂. In one embodiment,Z^(A) is SO₂NH and R₅ is CH₂CH(OH)CH₂OH. In one embodiment, Z^(A) isSO₂NH and R₅ is CH₂CH(OH)CH₂CH₃. In one embodiment, Z^(A) is SO₂NH andR₅ is C(CH₃)₂CH₂OH. In one embodiment, Z^(A) is SO₂NH and R₅ isCH(CH₂CH₃)CH₂OH. In one embodiment, Z^(A) is SO₂NH and R₅ isCH₂CH₂OCH₂CH₂OH. In one embodiment, Z^(A) is SO₂NH and R₅ isC(CH₃)(CH₂OH)₂. In one embodiment, Z^(A) is SO₂NH and R₅ isCH(CH₃)C(O)OH. In one embodiment, Z^(A) is SO₂NH and R₅ isCH(CH₂OH)C(O)OH. In one embodiment, Z^(A) is SO₂NH and R₅ is CH₂C(O)OH.In one embodiment, Z^(A) is SO₂NH and R₅ is CH₂CH₂C(O)OH. In oneembodiment, Z^(A) is SO₂NH and R₅ is CH₂CH(OH)CH₂C(O)OH. In oneembodiment, Z^(A) is SO₂NH and R₅ is CH₂CH₂N(CH₃)₂. In one embodiment,Z^(A) is SO₂NH and R₅ is CH₂CH₂NHC(O)CH₃. In one embodiment, Z^(A) isSO₂NH and R₅ is CH(CH(CH₃)₂)CH₂OH. In one embodiment, Z^(A) is SO₂NH andR₅ is CH(CH₂CH₂CH₃)CH₂OH. In one embodiment, Z^(A) is SO₂NH and R₅ istetrahydrofuran-2-ylmethyl. In one embodiment, Z^(A) is SO₂NH and R₅ isfurylmethyl. In one embodiment, Z^(A) is SO₂NH and R₅ is(5-methylfuryl)-methyl. In one embodiment, Z^(A) is SO₂NH and R₅ is2-pyrrolidinylethyl. In one embodiment, Z^(A) is SO₂NH and R₅ is2-(1-methylpyrrolidinyl)-ethyl. In one embodiment, Z^(A) is SO₂NH and R₅is 2-(morpholin-4-yl)-ethyl. In one embodiment, Z^(A) is SO₂NH and R₅ is3-(morpholin-4-yl)-propyl. In one embodiment, Z^(A) is SO₂NH and R₅ isC(CH₂CH₃)(CH₂OH)₂. In one embodiment, Z^(A) is SO₂NH and R₅ is2-(1H-imidazol-4-yl)ethyl. In one embodiment, Z^(A) is SO₂NH and R₅ is3-(1H-imidazol-1-yl)-propyl. In one embodiment, Z^(A) is SO₂NH and R₅ is2-(pyridin-2-yl)-ethyl.

In some embodiment, Z^(A) is SO₂NH and R₅ is an optionally substitutedC₃₋₈ cycloaliphatic. In several examples, Z^(A) is SO₂NH and R₅ is anoptionally substituted C₃₋₈ cycloalkyl. In several examples, Z^(A) isSO₂NH and R₅ is C₃₋₈ cycloalkyl. In one embodiment, Z^(A) is SO₂NH andR₅ is cyclobutyl. In one embodiment, Z^(A) is SO₂NH and R₅ iscyclopentyl. In one embodiment, Z^(A) is SO₂NH and R₅ is cyclohexyl.

In some embodiment, Z^(A) is SO₂NH and R₅ is an optionally substituted3-8 membered heterocycloaliphatic. In several examples, Z^(A) is SO₂NHand R₅ is an optionally substituted 3-8 membered heterocycloalkyl,having 1, 2, or 3 ring members independently selected from nitrogen(including NH and NR^(X)), oxygen, or sulfur (including S, SO, and SO₂).In several examples, Z^(A) is SO₂NH and R₅ is 3-8 memberedheterocycloalkyl optionally substituted with 1, 2, or 3 groupsindependently selected from oxo, halo, hydroxy, or an optionallysubstituted group selected from C₁₋₆ aliphatic, aryl, heteroaryl,carbonyl, amino, and carboxy. In one embodiment, Z^(A) is SO₂NH and R₅is 3-oxo-isoxazolidin-4-yl.

In some embodiments, Z^(A) is SO₂N(C₁₋₆ alkyl) and R₅ is an optionallysubstituted straight or branched C₁₋₆ aliphatic or an optionallysubstituted cycloaliphatic. In some embodiments, Z^(A) is SO₂N(C₁₋₆alkyl) and R₅ is an optionally substituted straight or branched C₁₋₆aliphatic. In some embodiments, Z^(A) is SO₂N(C₁₋₆ alkyl) and R₅ is anoptionally substituted straight or branched C₁₋₆ alkyl or an optionallysubstituted straight or branched C₂₋₆ alkenyl. In one embodiments, Z^(A)is SO₂N(CH₃) and R₅ is methyl. In one embodiments, Z^(A) is SO₂N(CH₃)and R₅ is n-propyl. In one embodiments, Z^(A) is SO₂N(CH₃) and R₅ isn-butyl. In one embodiments, Z^(A) is SO₂N(CH₃) and R₅ is cyclohexyl. Inone embodiments, Z^(A) is SO₂N(CH₃) and R₅ is allyl. In one embodiments,Z^(A) is SO₂N(CH₃) and R₅ is CH₂CH₂OH. In one embodiments, Z^(A) isSO₂N(CH₃) and R₅ is CH₂CH(OH)CH₂OH. In one embodiments, Z^(A) isSO₂N(ethyl) and R₅ is ethyl. In one embodiment, Z^(A) is SO₂N(CH₂CH₃)and R₅ is CH₂CH₃OH. In one embodiments, Z^(A) is SO₂N(CH₂CH₂CH₃) and R₅is cyclopropylmethyl. In one embodiments, Z^(A) is SO₂N(n-propyl) and R₅is n-propyl. In one embodiments, Z^(A) is SO₂N(iso-propyl) and R₅ isiso-propyl.

In some embodiments, Z^(A) is CH₂NHSO₂ and R₅ is an optionallysubstituted C₁₋₆ aliphatic. In some embodiments, Z^(A) is CH₂NHSO₂ andR₅ is an optionally substituted straight or branched C₁₋₆ alkyl. In oneembodiment, Z^(A) is CH₂NHSO₂ and R₅ is methyl, ethyl, n-propyl,iso-propyl, or n-butyl. In some embodiments, Z^(A) is CH₂N(C₁₋₆aliphatic)SO₂ and R₅ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, Z^(A) is CH₂N(C₁₋₆ aliphatic)SO₂ and R₅ is anoptionally substituted straight or branched C₁₋₆ alkyl. In oneembodiment, Z^(A) is CH₂N(CH₃)SO₂ and R₅ is methyl, ethyl, n-propyl,iso-propyl, or n-butyl.

In one embodiment, Z^(A) is SO and R₅ is methyl. In one embodiment,Z^(A) is SO₂ and R₅ is OH. In some embodiments, Z^(A) is SO₂ and R₅ isan optionally substituted straight or branched C₁₋₆ aliphatic or anoptionally substituted 3-8 membered heterocyclic, having 1, 2, or 3 ringmembers independently selected from the group consisting of nitrogen(including NH and NR^(X)), oxygen, or sulfur (including S, SO, and SO₂).In some embodiments, Z^(A) is SO₂ and R₅ is straight or branched C₁₋₆alkyl or 3-8 membered heterocycloaliphatic; each of which is optionallysubstituted with 1, 2, or 3 of oxo, halo, hydroxy, or an optionallysubstituted group selected from C₁₋₆ aliphatic, aryl, heteroaryl,carbonyl, amino, and carboxy. In one embodiment, Z^(A) is SO₂ and R₅ ismethyl, ethyl, or iso-propyl. In some embodiments, Z^(A) is SO₂ andexamples of R₅ include but are not limited to:

In one embodiment, Z^(A) is CO and R₅ is an optionally substitutedamino, an optionally substituted C₁₋₆ straight or branched aliphatic, oran optionally substituted 3-8 membered heterocyclic, having 1, 2, or 3ring members independently selected from the group consisting ofnitrogen (including NH and NR^(X)), oxygen, or sulfur (including S, SO,and SO₂). In one embodiment, Z^(A) is CO and R₅ isdi-(2-methoxyethyl)amino or di-(2-hydroxyethyl)amino. In someembodiments, Z^(A) is CO and R₅ is straight or branched C₁₋₆ alkyl or3-8 membered heterocycloaliphatic each of which is optionallysubstituted with 1, 2, or 3 of oxo, halo, hydroxy, or an optionallysubstituted group selected from C₁₋₆ aliphatic, aryl, heteroaryl,carbonyl, amino, and carboxy. In one embodiment, Z^(A) is CO and R₅ is

In some embodiments, Z^(A) is NHCO and R₅ is an optionally substitutedgroup selected from C₁₋₆ aliphatic, C₁₋₆ alkoxy, amino, andheterocycloaliphatic. In one embodiment, Z^(A) is NHCO and R₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, amino, or 3-8 membered heterocycloalkyl having 1, 2,or 3 ring member independently selected from nitrogen (including NH andNR^(X)), oxygen, or sulfur (including S, SO, and SO₂); wherein saidalkyl, alkoxy, amino or heterocycloalkyl each is optionally substitutedwith 1, 2, or 3 groups independently selected from oxo, halo, hydroxy,or an optionally substituted group selected from C₁₋₆ aliphatic, 3-8membered heterocycloaliphatic, alkoxy, carbonyl, amino, and carboxy. Inone embodiment, Z^(A) is NHCO and R₅ is methyl, methoxymethyl,hydroxymethyl, (morpholin-4-yl)-methyl, CH₂COOH, ethoxy, dimethylamino,or morpholin-4-yl.

In some embodiments, one R^(A) not attached at the carbon carbon 3″ or4″ is selected from the group consisting of H, R^(B), halo, —OH,—(CH₂)_(r)NR^(B)R^(B), —(CH₂)_(r)—OR^(B), —SO₂—R^(B), —NR^(B)—SO₂—R^(B),—SO₂NR^(B)R^(B), —C(O)R^(B), —C(O)OR^(B), —OC(O)OR^(B),—NR^(B)C(O)OR^(B), and —C(O)NR^(B)R^(B); wherein r is 0, 1, or 2; andeach R^(B) is independently hydrogen, an optionally substituted C₁₋₈aliphatic group, an optionally substituted cycloaliphatic, an optionallysubstituted heterocycloaliphatic, an optionally substituted aryl, or anoptionally substituted heteroaryl. In other embodiments, one R^(A) notattached at the carbon carbon 3″ or 4″ is selected from the groupconsisting of H, C₁₋₆ aliphatic, C₃₋₈ cycloaliphatic, 3-8 memberedheterocycloaliphatic, C6-10 aryl, 5-8 membered heteroaryl, halo, —CN,—NH₂, —NH(C₁₋₆ aliphatic), —N(C₁₋₆ aliphatic)₂, —CH₂—N(C₁₋₆ aliphatic)₂,—CH₂— (heteroaryl), —CH₂—NH(C₁₋₆ aliphatic), —CH₂NH₂, —OH, —O(C₁₋₆aliphatic), —CH₂OH, —CH₂—O(C₁₋₆ aliphatic), —SO₂(C₁₋₆ aliphatic),—N(C₁₋₆ aliphatic)-SO₂(C₁₋₆ aliphatic), —NH—SO₂(C₁₋₆ aliphatic),—SO₂NH₂, —SO₂NH(C₁₋₆ aliphatic), —SO₂N(C₁₋₆ aliphatic)₂, —C(O)(C₁₋₆aliphatic), —C(O)O(C₁₋₆ aliphatic), —C(O)OH, —OC(O)O(C₁₋₆ aliphatic),—NHC(O)(C₁₋₆ aliphatic), —NHC(O)O(C₁₋₆ aliphatic), —N(C₁₋₆aliphatic)C(O)O(C₁₋₆ aliphatic), —C(O)NH₂, and —C(O)N(C₁₋₆ aliphatic)₂.In several examples, R^(A2) is selected from the group consisting of H,C₁₋₆ aliphatic, 5-8 membered heteroaryl, halo, —CN, —NH₂, —CH₂NH₂, —OH,—O(C₁₋₆ aliphatic), —CH₂OH, —CH₂-(5-8 membered heteroaryl), —SO₂(C₁₋₆aliphatic), —NH—SO₂(C₁₋₆ aliphatic), —C(O)O(C₁₋₆ aliphatic), —C(O)OH,—NHC(O)(C₁₋₆ aliphatic), —C(O)NH₂, —C(O)NH(C₁₋₆ aliphatic), and—C(O)N(C₁₋₆ aliphatic)₂. For examples, one R^(A) not attached at thecarbon carbon 3″ or 4″ is selected from the group consisting of H,methyl, ethyl, n-propyl, iso-propyl, tert-butyl, tetrazol-5-yl, F, Cl,CN, —NH₂, —CH₂NH₂, —CH₂CN, —CH₂COOH, —CH₂CH₂COOH,1,3-dioxo-isoindolin-2-ylmethyl, —OH, —OCH₃, —OCF₃, ethoxy, iso-propoxy,n-propoxy, —CH₂OH, —CH₂CH₂OH, —SO₂CH₃, —NH—SO₂CH₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)OH, —NHC(O)CH₃, —C(O)NH₂, and —C(O)N(CH₃)₂. In oneembodiment, one R^(A) not attached at the carbon carbon 3″ or 4″ ishydrogen. In another embodiment, one R^(A) not attached at the carboncarbon 3″ or 4″ is methyl, ethyl, F, Cl, or —OCH₃.

In some embodiments, one R^(A) not attached at the carbon carbon 3″ or4″ is H, hydroxy, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₆ cycloalkyl, orNH₂. In several examples, R^(A2) is H, halo, C₁₋₄ alkyl, or C₁₋₄ alkoxy.Examples of one R^(A) not attached at the carbon carbon 3″ or 4″ includeH, F, Cl, methyl, ethyl, and methoxy.

5. Exemplary Compounds

Exemplary compounds of the present invention include, but are notlimited to, those illustrated in Table 1 below. TABLE 1 Examples ofcompounds of the present invention 1

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Synthetic Schemes

Compounds of the invention may be prepared by well-known methods in theart. Exemplary methods are illustrated below in Scheme I and Scheme II.

Referring to Scheme I, a nitrile of formula i is alkylated (step a) witha dihalo-aliphatic in the presence of a base such as, for example, 50%sodium hydroxide and, optionally, a phase transfer reagent such as, forexample, benzyltriethylammonium chloride (BTEAC), to produce thecorresponding alkylated nitrile (not shown) which on hydrolysis in situproduces the acid ii. Compounds of formula II may be converted to theacid chloride iii (step b) with a suitable reagent such as, for example,thionyl chloride/DMF. Reaction of the acid chloride iii with an anilineof formula iv under known conditions, (step c) produces the amidecompounds of the invention formula I. Alternatively, the acid ii may bereacted directly with the aniline iv (step d) in the presence of acoupling reagent such as, for example, HATU, under known conditions togive the amides I.

In some instances, when one of R₁ is a halogen, compounds of formula Imay be further modified as shown below in Scheme II.

Referring to Scheme II, reaction of the amide v, wherein X is halogen,with a boronic acid derivative vi (step e) wherein Z and Z′ areindependently H, alkyl or Z and Z′ together with the atoms to which theyare bound form a five or six membered optionally substitutedcycloaliphatic ring, in the presence of a catalyst such as, for example,palladium acetate ordichloro-[1,1-bis(diphenylphosphino)ferrocene]palladium(II)(Pd(dppf)Cl₂), provides compounds of the invention wherein one of R₁ isaryl or heteroaryl.

The phenylacetonitriles of formula i are commercially available or maybe prepared as shown in Scheme III.

Referring to Scheme III, wherein R represents substituents as describedfor R₄, the aryl bromide vii is converted to the ester viii with carbonmonoxide and methanol in the presence oftetrakis(triphenylphosphine)palladium (0). The ester viii is reduced tothe alcohol ix with a reducing reagent such as lithium aluminum hydride.The benzyl alcohol ix is converted to the corresponding benzylchloridewith, for example, thionyl chloride. Reaction of the benzylchloride xwith a cyanide, for example sodium cyanide, provides the startingnitriles i. Or the aldehyde xiv can also be converted into thecorresponding nitrile i by reaction with TosMIC reagent.

The aryl bromides vii are commercially available or may be prepared byknown methods.

In some instances, the anilines iv (Scheme I) wherein one of R₁ is arylor heteroaryl may be prepared as shown in Scheme IV.

Referring to Scheme IV, an aryl boronic acid xi is coupled with ananiline xii protected as, for example, a tert-butoxycarbonyl derivative(BOC), in the presence of a palladium reagent as previously describedfor Scheme II to give xiii. Removal of the protecting group under knownconditions such as aqueous HCl provides the desired substituted aniline.

Boronic acids are commercially available or may be prepared by knownmethods.

In some instances, R₁ and R₄ may contain functionality such as, forexample, a carboxylate, a nitrile or an amine, which may be furthermodified using known methods. For example, carboxylates may be convertedto amides or carbamates; amines may be converted to amides, sulfonamidesor carbamates; nitriles may be reduced to amino methyl compounds whichin turn may be further converted to amine derivatives.

Formulations, Administrations, and Uses

Pharmaceutically Acceptable Compositions

Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more, additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative or a prodrug thereof. Accordingto the present invention, a pharmaceutically acceptable derivative or aprodrug includes, but is not limited to, pharmaceutically acceptablesalts, esters, salts of such esters, or any other adduct or derivativewhich upon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describes pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersible products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, the present invention provides a method oftreating a condition, disease, or disorder implicated by ABC transporteractivity. In certain embodiments, the present invention provides amethod of treating a condition, disease, or disorder implicated by adeficiency of ABC transporter activity, the method comprisingadministering a composition comprising a compound of formula (I) to asubject, preferably a mammal, in need thereof.

In certain preferred embodiments, the present invention provides amethod of treating Cystic fibrosis, Hereditary emphysema, Hereditaryhemochromatosis, Coagulation-Fibrinolysis deficiencies, such as ProteinC deficiency, Type 1 hereditary angioedema, Lipid processingdeficiencies, such as Familial hypercholesterolemia, Type 1chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, suchas I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism,Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma,Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism,Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency,Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-MarieTooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Progressive supranuclear plasy, Pick's disease,several polyglutamine neurological disorders asuch as Huntington,Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,Dentatorubal pallidoluysian, and Myotonic dystrophy, as well asSpongiform encephalopathies, such as Hereditary Creutzfeldt-Jakobdisease (due to Prion protein processing defect), Fabry disease,Straussler-Scheinker disease, secretory diarrhea, polycystic kidneydisease, chronic obstructive pulmonary disease (COPD), dry eye disease,and Sjögren's Syndrome, comprising the step of administering to saidmammal an effective amount of a composition comprising a compound offormula (I), or a preferred embodiment thereof as set forth above.

According to an alternative preferred embodiment, the present inventionprovides a method of treating cystic fibrosis comprising the step ofadministering to said mammal a composition comprising the step ofadministering to said mammal an effective amount of a compositioncomprising a compound of formula (I), or a preferred embodiment thereofas set forth above.

According to the invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of one or more of Cystic fibrosis,Hereditary emphysema, Hereditary hemochromatosis,Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency,Type 1 hereditary angioedema, Lipid processing deficiencies, such asFamilial hypercholesterolemia, Type 1 chylomicronemia,Abetalipoproteinemia, Lysosomal storage diseases, such as I-celldisease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetesmellitus, Laron dwarfism, Myleoperoxidase deficiency, Primaryhypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditaryemphysema, Congenital hyperthyroidism, Osteogenesis imperfecta,Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,Perlizaeus-Merzbacher disease, neurodegenerative diseases such asAlzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis,Progressive supranuclear plasy, Pick's disease, several polyglutamineneurological disorders asuch as Huntington, Spinocerebullar ataxia typeI, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, andMyotonic dystrophy, as well as Spongiform encephalopathies, such asHereditary Creutzfeldt-Jakob disease, Fabry disease,Straussler-Scheinker disease, secretory diarrhea, polycystic kidneydisease, chronic obstructive pulmonary disease (COPD), dry eye disease,and Sjögren's Syndrome.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of Cystic fibrosis, Hereditary emphysema, Hereditaryhemochromatosis, Coagulation-Fibrinolysis deficiencies, such as ProteinC deficiency, Type 1 hereditary angioedema, Lipid processingdeficiencies, such as Familial hypercholesterolemia, Type 1chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, suchas I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism,Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma,Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism,Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency,Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-MarieTooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Progressive supranuclear plasy, Pick's disease,several polyglutamine neurological disorders asuch as Huntington,Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,Dentatorubal pallidoluysian, and Myotonic dystrophy, as well asSpongiform encephalopathies, such as Hereditary Creutzfeldt-Jakobdisease, Fabry disease, Straussler-Scheinker disease, secretorydiarrhea, polycystic kidney disease, chronic obstructive pulmonarydisease (COPD), dry eye disease, and Sjögren's Syndrome.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas modulators of ABC transporters. Thus, without wishing to be bound byany particular theory, the compounds and compositions are particularlyuseful for treating or lessening the severity of a disease, condition,or disorder where hyperactivity or inactivity of ABC transporters isimplicated in the disease, condition, or disorder. When hyperactivity orinactivity of an ABC transporter is implicated in a particular disease,condition, or disorder, the disease, condition, or disorder may also bereferred to as a “ABC transporter-mediated disease, condition ordisorder”. Accordingly, in another aspect, the present inventionprovides a method for treating or lessening the severity of a disease,condition, or disorder where hyperactivity or inactivity of an ABCtransporter is implicated in the disease state.

The activity of a compound utilized in this invention as a modulator ofan ABC transporter may be assayed according to methods describedgenerally in the art and in the Examples herein.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to modulating ABC transporteractivity in a biological sample or a patient (e.g., in vitro or invivo), which method comprises administering to the patient, orcontacting said biological sample with a compound of formula I or acomposition comprising said compound. The term “biological sample”, asused herein, includes, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof.

Modulation of ABC transporter activity in a biological sample is usefulfor a variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, the study ofABC transporters in biological and pathological phenomena; and thecomparative evaluation of new modulators of ABC transporters.

In yet another embodiment, a method of modulating activity of an anionchannel in vitro or in vivo, is provided comprising the step ofcontacting said channel with a compound of formula (I). In preferredembodiments, the anion channel is a chloride channel or a bicarbonatechannel. In other preferred embodiments, the anion channel is a chloridechannel.

According to an alternative embodiment, the present invention provides amethod of increasing the number of functional ABC transporters in amembrane of a cell, comprising the step of contacting said cell with acompound of formula (I). The term “functional ABC transporter” as usedherein means an ABC transporter that is capable of transport activity.In preferred embodiments, said functional ABC transporter is CFTR.

According to another preferred embodiment, the activity of the ABCtransporter is measured by measuring the transmembrane voltagepotential. Means for measuring the voltage potential across a membranein the biological sample may employ any of the known methods in the art,such as optical membrane potential assay or other electrophysiologicalmethods.

The optical membrane potential assay utilizes voltage-sensitive FRETsensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y.Tsien (1995) “Voltage sensing by fluorescence resonance energy transferin single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

These voltage sensitive assays are based on the change in fluorescenceresonant energy transfer (FRET) between the membrane-soluble,voltage-sensitive dye, DiSBAC₂(3), and a fluorescent phospholipid,CC2-DMPE, which is attached to the outer leaflet of the plasma membraneand acts as a FRET donor. Changes in membrane potential (V_(m)) causethe negatively charged DiSBAC₂(3) to redistribute across the plasmamembrane and the amount of energy transfer from CC2-DMPE changesaccordingly. The changes in fluorescence emission can be monitored usingVIPR™ II, which is an integrated liquid handler and fluorescent detectordesigned to conduct cell-based screens in 96- or 384-well microtiterplates.

In another aspect the present invention provides a kit for use inmeasuring the activity of a ABC transporter or a fragment thereof in abiological sample in vitro or in vivo comprising (i) a compositioncomprising a compound of formula (I) or any of the above embodiments;and (ii) instructions for a.) contacting the composition with thebiological sample and b.) measuring activity of said ABC transporter ora fragment thereof. In one embodiment, the kit further comprisesinstructions for a.) contacting an additional composition with thebiological sample; b.) measuring the activity of said ABC transporter ora fragment thereof in the presence of said additional compound, and c.)comparing the activity of the ABC transporter in the presence of theadditional compound with the density of the ABC transporter in thepresence of a composition of formula (I). In preferred embodiments, thekit is used to measure the density of CFTR.

PREPARATIONS AND EXAMPLES

Preparation 1: 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (A-8)

A mixture of benzo[1,3]dioxole-5-acetonitrile (5.10 g 31.7 mmol),1-bromo-2-chloro-ethane (9.00 mL 109 mmol), and benzyltriethylammoniumchloride (0.181 g, 0.795 mmol) was heated at 70° C. and then 50%(wt./wt.) aqueous sodium hydroxide (26 mL) was slowly added to themixture. The reaction was stirred at 70° C. for 24 hours and was thenheated at 130° C. for 48 hours. The dark brown reaction mixture wasdiluted with water (400 mL) and extracted once with an equal volume ofethyl acetate and once with an equal volume of dichloromethane. Thebasic aqueous solution was acidified with concentrated hydrochloric acidto pH less than one and the precipitate was filtered and washed with 1 Mhydrochloric acid. The solid material was dissolved in dichloromethane(400 mL) and extracted twice with equal volumes of 1 M hydrochloric acidand once with a saturated aqueous solution of sodium chloride. Theorganic solution was dried over sodium sulfate and evaporated to drynessto give a white to slightly off-white solid (5.23 g, 80%) ESI-MS m/zcalc. 206.1, found 207.1 (M+1)⁺. Retention time 2.37 minutes. ¹H NMR(400 MHz, DMSO-d₆) δ 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H),6.79 (m, 2H), 6.88 (m, 1H), 12.26 (s, 1H).

Preparation 2:1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-9)

Step a: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester

A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol)and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh₃)₄, 5.78 g, 5.00mmol] in methanol (20 mL) containing acetonitrile (30 mL) andtriethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55PSI) at 75° C. (oil bath temperature) for 15 hours. The cooled reactionmixture was filtered and the filtrate was evaporated to dryness. Theresidue was purified by silica gel column chromatography to give crude2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g),which was used directly in the next step.

Step b: (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-methanol

Crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester(11.5 g) dissolved in 20 mL of anhydrous tetrahydrofuran (THF) wasslowly added to a suspension of lithium aluminum hydride (4.10 g, 106mmol) in anhydrous THF (100 mL) at 0° C. The mixture was then warmed toroom temperature. After being stirred at room temperature for 1 hour,the reaction mixture was cooled to 0° C. and treated with water (4.1 g),followed by sodium hydroxide (10% aqueous solution, 4.1 mL). Theresulting slurry was filtered and washed with THF. The combined filtratewas evaporated to dryness and the residue was purified by silica gelcolumn chromatography to give(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 76% over twosteps) as a colorless oil.

Step c: 5-Chloromethyl-2,2-difluoro-benzo[1,3]dioxole

Thionyl chloride (45 g, 38 mmol) was slowly added to a solution of(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol) indichloromethane (200 mL) at 0° C. The resulting mixture was stirredovernight at room temperature and then evaporated to dryness. Theresidue was partitioned between an aqueous solution of saturated sodiumbicarbonate (100 mL) and dichloromethane (100 mL). The separated aqueouslayer was extracted with dichloromethane (150 mL) and the organic layerwas dried over sodium sulfate, filtrated, and evaporated to dryness togive crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) whichwas used directly in the next step.

Step d: (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile

A mixture of crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g)and sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 mL) wasstirred at room temperature overnight. The reaction mixture was pouredinto ice and extracted with ethyl acetate (300 mL). The organic layerwas dried over sodium sulfate and evaporated to dryness to give crude(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (3.3 g) which was useddirectly in the next step.

Step e: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile

Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to amixture of crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile,benzyltriethylammonium chloride (3.00 g, 15.3 mmol), and1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70° C. The mixture wasstirred overnight at 70° C. before the reaction mixture was diluted withwater (30 mL) and extracted with ethyl acetate. The combined organiclayers were dried over sodium sulfate and evaporated to dryness to givecrude 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile,which was used directly in the next step.

Step f: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylicacid (A-9)

To 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile(crude from the last step) was added 10% aqueous sodium hydroxide (50mL) and the mixture was heated at reflux for 2.5 hours. The cooledreaction mixture was washed with ether (100 mL) and the aqueous phasewas acidified to pH 2 with 2M hydrochloric acid. The precipitated solidwas filtered to give1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as awhite solid (0.15 g, 2% over four steps). ESI-MS m/z calc. 242.2, found243.3; ¹H NMR (CDCl₃) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m, 1H), 1.74-1.64(m, 2H), 1.26-1.08 (m, 2H).

Preparation 3: 2-(4-(Benzyloxy)-3-chlorophenyl)acetonitrile

Step a: 4-Benzyloxy-3-chloro-benzaldehyde

To a solution of 3-chloro-4-hydroxy-benzaldehyde (5.0 g, 32 mmol) andBnBr (6.6 g, 38 mmol) in CH₃CN (100 mL) was added K₂CO₃ (8.8 g, 64mmol). The mixture was heated at reflux for 2 hours. The resultingmixture was poured into water (100 mL), and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine, dried overanhydrous Na₂SO₄ and evaporated under vacuum to give crude product,which was purified by column (petroleum ether/EtOAc 15:1) to give4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 95%). ¹H NMR (CDCl₃, 400 MHz)δ 9.85 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.73 (dd, J=2.0, 8.4 Hz, 1H),7.47-7.34 (m, 5H), 7.08 (d, J=8.8 Hz, 1H), 4.26 (s, 2H).

Step b: 2-(4-(Benzyloxy)-3-chlorophenyl)acetonitrile

To a suspension of t-BuOK (11.7 g, 96 mmol) in THF (200 mL) was added asolution of TosMIC (9.4 g, 48 mmol) in THF (100 mL) at −78° C. Themixture was stirred for 15 minutes, treated with a solution of4-benzyloxy-3-chloro-benzaldehyde (7.5 g, 30 mmol) in THF (50 mL)dropwise, and continued to stir for 1.5 hours at −78° C. To the cooledreaction mixture was added methanol (30 mL). The mixture was heated atreflux for 30 minutes. Solvent of the reaction mixture was removed togive a crude product, which was dissolved in water (300 mL). The aqueousphase was extracted with EtOAc (3×100 mL). The combined organic layerswere dried and evaporated under reduced pressure to give crude product,which was purified by column chromatography (petroleum ether/EtOAc 10:1)to afford 2-(4-(benzyloxy)-3-chlorophenyl)acetonitrile (2.7 g, 34%). ¹HNMR (400 MHz, CDCl₃) δ 7.52-7.32 (m, 6H), 7.15 (dd, J=2.4, 8.4 Hz, 1H),6.95 (d, J=8.4 Hz, 1H), 5.26 (s, 2H), 3.73 (s, 2H). ¹³C NMR (100 MHz,CDCl₃) δ 154.0, 136.1, 129.9, 128.7, 128.7, 128.1, 127.2, 127.1, 127.1,124.0, 123.0, 117.5, 114.4, 70.9, 22.5.

Preparation 4:1-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropane-carboxylic acid(A-19)

Step a: 1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester

To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50.0g, 0.26 mol) in MeOH (500 mL) was added toluene-4-sulfonic acidmonohydrate (2.5 g, 13.1 mmol) at room temperature. The reaction mixturewas heated at reflux for 20 hours. MeOH was removed by evaporation undervacuum and EtOAc (200 mL) was added. The organic layer was washed withsat. aq. NaHCO₃ (100 mL) and brine, dried over anhydrous Na₂SO₄ andevaporated under vacuum to give1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (53.5 g,99%). ¹H NMR (CDCl₃, 400 MHz) δ 7.25-7.27 (m, 2H), 6.85 (d, J=8.8 Hz,2H), 3.80 (s, 3H), 3.62 (s, 3H), 1.58 (q, J=3.6 Hz, 2H), 1.15 (q, J=3.6Hz, 2H).

Step b: 1-(4-Methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methylester

To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid methylester (30.0 g, 146 mmol) in Ac₂O (300 mL) was added a solution of HNO₃(14.1 g, 146 mmol, 65%) in AcOH (75 mL) at 0° C. The reaction mixturewas stirred at 0˜5° C. for 3 h before aq. HCl (20%) was added dropwiseat 0° C. The resulting mixture was extracted with EtOAc (200 mL×3). Theorganic layer was washed with sat. aq. NaHCO₃ then brine, dried overanhydrous Na₂SO₄ and evaporated under vacuum to give1-(4-methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester(36.0 g, 98%), which was directly used in the next step. ¹H NMR (CDCl₃,300 MHz) δ 7.84 (d, J=2.1 Hz, 1H), 7.54 (dd, J=2.1, 8.7 Hz, 1H), 7.05(d, J=8.7 Hz, 1H), 3.97 (s, 3H), 3.65 (s, 3H), 1.68-1.64 (m, 2H),1.22-1.18 (m, 2H).

Step c: 1-(4-Hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methylester

To a solution of 1-(4-methoxy-3-nitro-phenyl)-cyclopropane-carboxylicacid methyl ester (10.0 g, 39.8 mmol) in CH₂Cl₂ (100 mL) was added BBr₃(12.0 g, 47.8 mmol) at −70° C. The mixture was stirred at −70° C. for 1hour, then allowed to warm to −30° C. and stirred at this temperaturefor 3 hours. Water (50 mL) was added dropwise at −20° C., and theresulting mixture was allowed to warm room temperature before it wasextracted with EtOAc (200 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄ and evaporated under vacuum to give the crudeproduct, which was purified by column chromatography on silica gel(petroleum ether/EtOAc 15:1) to afford1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester(8.3 g, 78%). ¹H NMR (CDCl₃, 400 MHz) δ 10.5 (s, 1H), 8.05 (d, J=2.4 Hz,1H), 7.59 (dd, J=2.0, 8.8 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 3.64 (s, 3H),1.68-1.64 (m, 2H), 1.20-1.15 (m, 2H).

Step d: 1-(3-Amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methylester

To a solution of 1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylicacid methyl ester (8.3 g, 35.0 mmol) in MeOH (100 mL) was added Raney Ni(0.8 g) under nitrogen atmosphere. The mixture was stirred underhydrogen atmosphere (1 atm) at 35° C. for 8 hours. The catalyst wasfiltered off through a Celite pad and the filtrate was evaporated undervacuum to give crude product, which was purified by columnchromatography on silica gel (P.E./EtOAc 1:1) to give1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester(5.3 g, 74%). ¹H NMR (CDCl₃, 400 MHz) δ 6.77 (s, 1H), 6.64 (d, J=2.0 Hz,2H), 3.64 (s, 3H), 1.55-1.52 (m, 2H), 1.15-1.12 (m, 2H).

Step e: 1-(2-Oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylicacid methyl ester

To a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylicacid methyl ester (2.0 g, 9.6 mmol) in THF (40 mL) was added triphosgene(4.2 g, 14 mmol) at room temperature. The mixture was stirred for 20minutes at this temperature before water (20 mL) was added dropwise at0° C. The resulting mixture was extracted with EtOAc (100 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ and evaporatedunder vacuum to give1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acidmethyl ester (2.0 g, 91%), which was directly used in the next step. ¹HNMR (CDCl₃, 300 MHz) δ 8.66 (s, 1H), 7.13-7.12 (m, 2H), 7.07 (s, 1H),3.66 (s, 3H), 1.68-1.65 (m, 2H), 1.24-1.20 (m, 2H).

Step f: 1-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylicacid

To a solution of1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acidmethyl ester (1.9 g, 8.1 mmol) in MeOH (20 mL) and water (2 mL) wasadded LiOH.H₂O (1.7 g, 41 mmol) in portions at room temperature. Thereaction mixture was stirred for 20 hours at 50° C. MeOH was removed byevaporation under vacuum before water (100 mL) and EtOAc (50 mL) wereadded. The aqueous layer was separated, acidified with HCl (3 mol/L) andextracted with EtOAc (100 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄ and evaporated under vacuum to give1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (1.5g, 84%). ¹H NMR (DMSO, 400 MHz) δ 12.32 (brs, 1H), 11.59 (brs, 1H), 7.16(d, J=8.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 1.44-1.41 (m, 2H), 1.13-1.10(m, 2H). MS (ESI) m/e (M+H⁺) 218.1.

Preparation 5: 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (A-20)

Step a: 1-Benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester

To a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylicacid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethylorthoformate (5.30 g, 14.5 mmol) and a catalytic amount ofp-toluenesulfonic acid monohydrate (0.3 g) at room temperature. Themixture was stirred for 3 hours at room temperature. The mixture wasdiluted with water and extracted with EtOAc (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and evaporated undervacuum to give crude 1-benzooxazol-5-yl-cyclopropanecarboxylic acidmethyl ester (3.1 g), which was directly used in the next step. ¹H NMR(CDCl₃, 400 MHz) δ 8.09 (s, 1), 7.75 (d, J=1.2 Hz, 1H), 7.53-7.51 (m,1H), 7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m, 2H), 1.27-1.24 (m,2H).

Step b: 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid

To a solution of crude 1-benzooxazol-5-yl-cyclopropanecarboxylic acidmethyl ester (2.9 g) in EtSH (30 mL) was added AlCl₃ (5.3 g, 40.1 mmol)in portions at 0° C. The reaction mixture was stirred for 18 hours atroom temperature. Water (20 mL) was added dropwise at 0° C. Theresulting mixture was extracted with EtOAc (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and evaporated undervacuum to give the crude product, which was purified by columnchromatography on silica gel (petroleum ether/EtOAc 1:2) to give1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280 mg, two steps:11%). ¹H NMR (DMSO, 400 MHz) δ 12.25 (brs, 1H), 8.71 (s, 1H), 7.70-7.64(m, 2H), 7.40 (dd, J=1.6, 8.4 Hz, 1H), 1.49-1.46 (m, 2H), 1.21-1.18 (m,2H). MS (ESI) m/e (M+H⁺) 204.4.

Preparation 6: 2-(7-Chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile

Step a: 3-Chloro-4,5-dihydroxybenzaldehyde

To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54mmol) in dichloromethane (300 mL) was added BBr₃ (26.7 g, 107 mmol)dropwise at −40° C. under N₂. After addition, the mixture was stirred atthis temperature for 5 h and then was poured into ice water. Theprecipitated solid was filtered and washed with petroleum ether. Thefiltrate was evaporated under reduced pressure to afford3-chloro-4,5-dihydroxybenzaldehyde (9.8 g, 89%), which was directly usedin the next step.

Step b: 7-Chlorobenzo[d][1,3]dioxole-5-carbaldehyde

To a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g, 46 mmol) andBrClCH₂ (23.9 g, 185 mmol) in dry DMF (100 mL) was added Cs₂CO₃ (25 g,190 mmol). The mixture was stirred at 60° C. overnight and was thenpoured into water. The resulting mixture was extracted with EtOAc (50mL×3). The combined extracts were washed with brine (100 mL), dried overNa₂SO₄ and concentrated under reduced pressure to afford7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 70%). ¹H NMR (400MHz, CDCl₃) δ 9.74 (s, 1H), 7.42 (d, J=0.4 Hz, 1H), 7.26 (d, J=3.6 Hz,1H), 6.15 (s, 2H)

Step c: (7-Chlorobenzo[d][1,3]dioxol-5-yl)methanol

To a solution of 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 33mmol) in THF (50 mL) was added NaBH₄ (2.5 g, 64 mmol)) in portion at 0°C. The mixture was stirred at this temperature for 30 min and thenpoured into aqueous NH₄Cl solution. The organic layer was separated, andthe aqueous phase was extracted with EtOAc (50 mL×3). The combinedextracts were dried over Na₂SO₄ and evaporated under reduced pressure toafford (7-chlorobenzo[d][1,3]dioxol-5-yl)methanol, which was directlyused in the next step.

Step d: 4-Chloro-6-(chloromethyl)benzo[d][1,3]dioxole

A mixture of (7-chlorobenzo[d][1,3]dioxol-5-yl)methanol (5.5 g, 30 mmol)and SOCl₂ (5.0 mL, 67 mmol) in dichloromethane (20 mL) was stirred atroom temperature for 1 h and was then poured into ice water. The organiclayer was separated and the aqueous phase was extracted withdichloromethane (50 mL×3). The combined extracts were washed with waterand aqueous NaHCO₃ solution, dried over Na₂SO₄ and evaporated underreduced pressure to afford4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole, which was directly usedin the next step.

Step e: 2-(7-Chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile

A mixture of 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole (6.0 g, 29mmol) and NaCN (1.6 g, 32 mmol) in DMSO (20 mL) was stirred at 40° C.for 1 h and was then poured into water. The mixture was extracted withEtOAc (30 mL×3). The combined organic layers were washed with water andbrine, dried over Na₂SO₄ and evaporated under reduced pressure to afford2-(7-chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile (3.4 g, 58%). ¹H NMR δ6.81 (s, 1H), 6.71 (s, 1H), 6.07 (s, 2H), 3.64 (s, 2H). ¹³C-NMR 6149.2,144.3, 124.4, 122.0, 117.4, 114.3, 107.0, 102.3, 23.1.

Preparation 7: 2-(7-Fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile

Step a: 3-Fluoro-4,5-dihydroxy-benzaldehyde

To a suspension of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.35 g,7.94 mmol) in dichloromethane (100 mL) was added BBr₃ (1.5 mL, 16 mmol)dropwise at −78° C. under N₂. After addition, the mixture was warmed to−30° C. and it was stirred at this temperature for 5 h. The reactionmixture was poured into ice water. The precipitated solid was collectedby filtration and washed with dichloromethane to afford3-fluoro-4,5-dihydroxy-benzaldehyde (1.1 g, 89%), which was directlyused in the next step.

Step b: 7-Fluoro-benzo[1,3]dioxole-5-carbaldehyde

To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol)and BrClCH₂ (4.9 g, 38.5 mmol) in dry DMF (50 mL) was added Cs₂CO₃ (12.6g, 39 mmol). The mixture was stirred at 60° C. overnight and was thenpoured into water. The resulting mixture was extracted with EtOAc (50mL×3). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄ and evaporated under reduced pressure to give thecrude product, which was purified by column chromatography on silica gel(petroleum ether/E.A.=10/1) to afford7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 49%). ¹H NMR (300MHz, CDCl₃) δ 9.78 (d, J=0.9 Hz, 1H), 7.26 (dd, J=1.5, 9.3 Hz, 1H), 7.19(d, J=1.2 Hz, 1H), 6.16 (s, 2H).

Step c: (7-Fluoro-benzo[1,3]dioxol-5-yl)-methanol

To a solution of 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 4.7mmol) in MeOH (50 mL) was added NaBH₄ (0.36 g, 9.4 mmol) in portions at0° C. The mixture was stirred at this temperature for 30 min and wasthen concentrated to dryness. The residue was dissolved in EtOAc. TheEtOAc layer was washed with water, dried over Na₂SO₄ and concentrated todryness to afford (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g,98%), which was directly used in the next step.

Step d: 6-Chloromethyl-4-fluoro-benzo[1,3]dioxole

To SOCl₂ (20 mL) was added (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol(0.80 g, 4.7 mmol) in portions at 0° C. The mixture was warmed to roomtemperature over 1 h and then was heated at reflux for 1 h. The excessSOCl₂ was evaporated under reduced pressure to give the crude product,which was basified with saturated aqueous NaHCO₃ to pH ˜7. The aqueousphase was extracted with EtOAc (50 mL×3). The combined organic layerswere dried over Na₂SO₄ and evaporated under reduced pressure to give6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 92%), which wasdirectly used in the next step.

Step e: 2-(7-Fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile

A mixture of 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 4.3mmol) and NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was stirred at 30° C.for 1 h and was then poured into water. The mixture was extracted withEtOAc (50 mL×3). The combined organic layers were washed with water (50mL) and brine (50 mL), dried over Na₂SO₄ and evaporated under reducedpressure to give the crude product, which was purified by columnchromatography on silica gel (petroleum ether/E.A.=10/1) to afford2-(7-fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (530 mg, 70%). ¹H NMR(300 MHz, CDCl₃) δ 6.68-6.64 (m, 2H), 6.05 (s, 2H), 3.65 (s, 2H).¹³C-NMR δ151.1, 146.2, 134.1, 124.2, 117.5, 110.4, 104.8, 102.8, 23.3.

Additional acids given in Table 2 were either commercially available orsynthesized using appropriate starting materials and the procedures ofpreparations 1-7. TABLE 2 Carboxylic Acids. Acids Name A-11-Phenylcyclopropanecarboxylic acid A-21-(2-Methoxyphenyl)cyclopropanecarboxylic acid A-31-(3-Methoxyphenyl)cyclopropanecarboxylic acid A-41-(4-Methoxyphenyl)cyclopropanecarboxylic acid A-51-(4-(Trifluoromethoxy)phenyl)cyclopropanecarboxylic acid A-61-(4-Chlorophenyl)cyclopropanecarboxylic acid A-71-(3,4-Dimethoxyphenyl)cyclopropanecarboxylic acid A-81-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid A-91-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)- cyclopropanecarboxylic acid A-101-Phenylcyclopentanecarboxylic acid A-111-(4-Chlorophenyl)cyclopentanecarboxylic acid A-121-(4-Methoxyphenyl)cyclopentanecarboxylic acid A-131-(Benzo[d][1,3]dioxol-5-yl)cyclopentanecarboxylic acid A-141-Phenylcyclohexanecarboxylic acid A-151-(4-Chlorophenyl)cyclohexanecarboxylic acid A-161-(4-Methoxyphenyl)cyclohexanecarboxylic acid A-174-(4-Methoxyphenyl)tetrahydro-2H-pyran-4-carboxylic acid A-181-(3-Chloro-4-hydroxyphenyl)cyclopropanecarboxylic acid A-191-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5- yl)cyclopropanecarboxylic acidA-20 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid A-211-(7-Chlorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxylic acid A-221-(7-Fluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxylic acid A-231-(3,4-Difluorophenyl)cyclopropanecarboxylic acid A-241-(1H-Indol-5-yl)cyclopropanecarboxylic acid A-251-(2,3-Dihydrobenzo[b][1,4]dioxin-6- yl)cyclopropanecarboxylic acid A-261-(2,3-Dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid A-271-(3,4-Dichlorophenyl)cyclopropanecarboxylic acid A-281-(2-Methyl-1H-benzo[d]imidazol-5- yl)cyclopropanecarboxylic acid A-291-(4-Hydroxy-4-methoxychroman-6- yl)cyclopropanecarboxylic acid A-301-(Benzofuran-6-yl)cyclopropanecarboxylic acid A-311-(1-Methyl-1H-benzo[d][1,2,3]triazol-5- yl)cyclopropanecarboxylic acidA-32 1-(2,3-Dihydrobenzofuran-6-yl)cyclopropanecarboxylic acid A-331-(3-Methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid A-341-(4-Oxochroman-6-yl)cyclopropanecarboxylic acid A-351-(Spiro[benzo[d][1,3]dioxole-2,1′-cyclobutane]-5-yl)cyclopropanecarboxylic acid A-361-(1,3-Dihydroisobenzofuran-5-yl)cyclopropanecarboxylic acid A-371-(6-Fluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxylic acid A-381-(Chroman-6-yl)cyclopropanecarboxylic acid

Preparation 8: 3-Bromo-4-methoxybenzenamine

2-Bromo-1-methoxy-4-nitrobenzene (2.50 g, 10.8 mmol), SnCl₂.2H₂O (12.2g, 53.9 mmol), and MeOH (30 mL) were combined and allowed to stir for 3h at ambient temperature. To the mixture was added H₂O (100 mL) andEtOAc (100 mL) resulting in the formation of a thick emulsion. To thiswas added sat. aq. NaHCO₃ (30 mL). The layers were separated and theaqueous layer was extracted with EtOAc (3×30 mL). The organics werecombined and dried over MgSO₄ before being filtered. Concentration ofthe filtrate in vacuo gave 2.02 g of an off-white solid. This materialwas used without further purification.

In addition to bromo-anilines prepared according to preparation 8,non-limiting examples of commercially available bromo anilines and bromonitrobenzenes are given in Table 3. TABLE 3 Non-limiting examples ofcommercially available anilines. Name 4-Bromoaniline4-Bromo-3-methylaniline 4-Bromo-3-(trifluoromethyl)aniline3-Bromoaniline 5-Bromo-2-methylaniline 5-Bromo-2-fluoroaniline5-Bromo-2-(trifluoromethoxy)aniline 3-Bromo-4-methylaniline3-Bromo-4-fluoroaniline 2-Bromo-1-methoxy-4-nitrobenzene2-Bromo-1-chloro-4-nitrobenzene 4-Bromo-3-methylaniline3-Bromo-4-methylaniline 3-Bromo-4-(trifluoromethoxy)aniline3-Bromo-5-(trifluoromethyl)aniline 3-Bromo-2-methylaniline

Preparation 9:1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)cyclopropane-carboxamide(B-10)

Step a: 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl chloride

To an oven-dried round bottom flask containing1-(benzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-8) (618 mg,3.0 mmol) and CH₂Cl₂ (3 mL) was added thionyl chloride (1.07 g, 9.0mmol) and N,N-dimethylformamide (0.1 mL). The reaction mixture wasstirred at ambient temperature under an Ar atmosphere until the gasevolution ceased (2-3 h). The excess thionyl chloride was removed undervacuum and the resulting residue dissolved in CH₂Cl₂ (3 mL). The mixturewas used without further manipulation.

Step b:1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)-cyclopropane-carboxamide(B-10)

To a solution of the crude 1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonylchloride (3.0 mmol) in CH₂Cl₂ (30 mL) at ambient temperature was added asolution of 3-bromo-4-methoxybenzenamine (3.3 mmol), Et₃N (15 mmol), andCH₂Cl₂ (90 mL) dropwise. The mixture was allowed to stir for 16 h beforeit was diluted with CH₂Cl₂ (500 mL). The solution was washed with 1N HCl(2×250 mL), sat. aq. NaHCO₃ (2×250 mL), then brine (250 mL). Theorganics were dried over Na₂SO₄, filtered, and concentrated in vacuo toprovide1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methoxyphenyl)cyclopropanecarboxamide(B-10) with suitable purity to be used without further purification.

Table 4 lists additional N-bromophenyl amides prepared according topreparation 9 and using appropriate starting materials.

Table 4: N-bromophenyl amides prepared according to preparation 9 andusing appropriate starting materials. Aryl bromides Name Anilines B-11-(Benzo[d][1,3]dioxol-5-yl)-N-(4- 4-Bromoanilinebromophenyl)cyclopropanecarboxamide B-21-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromo-3- 4-Bromo-3-methylanilinemethylphenyl)cyclopropanecarboxamide B-31-(Benzo[d][1,3]dioxol-5-yl)-N-(4-bromo-3- 4-Bromo-3-(trifluoromethyl)phenyl)cyclopropanecarboxamide (trifluoromethyl)anilineB-4 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3- 3-Bromoanilinebromophenyl)cyclopropanecarboxamide B-51-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-2- 5-Bromo-2-methylanilinemethylphenyl)cyclopropanecarboxamide B-61-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-2- 5-Bromo-2-fluoroanilinefluorophenyl)cyclopropanecarboxamide B-71-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-2- 5-Bromo-2-(trifluoromethoxy)phenyl)cyclopropanecarboxamide(trifluoromethoxy)aniline B-8 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-3-Bromo-4-methylaniline methylphenyl)cyclopropanecarboxamide B-91-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-fluoroanilinefluorophenyl)cyclopropanecarboxamide B-101-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-methoxyphenyl)cyclopropanecarboxamide methoxybenzenamine B-111-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-chloroanilinechlorophenyl)cyclopropanecarboxamide B-131-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-isopropylphenyl)cyclopropanecarboxamide isopropylaniline B-14N-(4-Bromo-3-methylphenyl)-1-(2,2- 4-Bromo-3-methylanilinedifluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamide B-15N-(3-Bromo-4-methylphenyl)-1-(2,2- 3-Bromo-4-methylanilinedifluorobenzo[d][1,3]dioxol-5- yl)cyclopropanecarboxamide B-161-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-tert-tert-butylphenyl)cyclopropanecarboxamide butylaniline B-181-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-ethylanilineethylphenyl)cyclopropanecarboxamide B-191-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4- 3-Bromo-4-(trifluoromethoxy)phenyl)cyclopropanecarboxamide(trifluoromethoxy)aniline B-201-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-2- 5-Bromo-2-fluoro-4-fluoro-4-methylphenyl)cyclopropanecarboxamide methylaniline B-211-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-5- 3-Bromo-5-(trifluoromethyl)phenyl)cyclopropanecarboxamide (trifluoromethyl)anilineB-22 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-2- 3-Bromo-2-methylanilinemethylphenyl)cyclopropanecarboxamide B-23N-(3-Bromo-4-(3-methyloxetan-3-yl)phenyl)-1- 3-Bromo-4-(3-(2,2-difluorobenzo[d][1,3]dioxol-5- methyloxetan-3-yl)anilineyl)cyclopropanecarboxamide B-24 N-(3-Bromo-4-methylphenyl)-1-(4-3-Bromo-4-methylaniline methoxyphenyl)cyclopropanecarboxamide

Preparation 10: ((3′-Aminobiphenyl-4-yl)methyl)-methanesulfonamide (C-1)

Step a: (4′-Cyano-biphenyl-3-yl)-carbamic acid tert-butyl ester

A mixture of 4-cyanobenzeneboronic acid (14.7 g, 0.10 mol),3-bromo-phenyl-carbamic acid tert-butyl ester (27.2 g, 0.10 mol),Pd(Ph₃P)₄ (11.6 g, 0.01 mol) and K₂CO₃ (21 g, 0.15 mol) in DMF/H₂O (1:1,350 mL) was stirred under argon at 80° C. overnight. The DMF wasevaporated under reduced pressure, and the residue was dissolved inEtOAc (200 mL). The mixture was washed with water and brine, dried overNa₂SO₄, and concentrated to dryness. The residue was purified by columnchromatography (petroleum ether/EtOAc 50:1) on silica gel to give(4′-cyano-biphenyl-3-yl)-carbamic acid tert-butyl ester (17 g, 59%). ¹HNMR (300 MHz, DMSO-d₆) δ 9.48 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.85 (s,1H), 7.76 (d, J=8.4 Hz, 2H), 7.32-7.48 (m, 3H), 1.47 (s, 9H).

Step b: (4′-Aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester

A suspension of (4′-cyano-biphenyl-3-yl)-carbamic acid tert-butyl ester(7.6 g, 26 mmol) and Raney Ni (1 g) in EtOH (500 mL) and NH₃.H₂O (10 mL)was hydrogenated under 50 psi of H₂ at 50° C. for 6 h. The catalyst wasfiltered off and the filtrate was concentrated to dryness to give(4′-aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester, which wasused directly in next step.

Step c: [4′-(Methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acidtert-butyl ester

To a solution of crude (4′-aminomethyl-biphenyl-3-yl)-carbamic acidtert-butyl ester (8.2 g 27 mmol) and Et₃N (4.2 g, 40 mmol) indichloromethane (250 mL) was added dropwise MsCl (3.2 g, 27 mmol) at 0°C. The reaction mixture was stirred at this temperature for 30 min andwas then washed with water and saturated aqueous NaCl solution, driedover Na₂SO₄, and concentrated to dryness. The residue was recrystallizedwith DCM/pet ether (1:3) to give[4′-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamic acidtert-butyl ester (7.5 g, yield 73%). ¹H NMR (300 MHz, CDCl₃) δ 7.67 (s,1H), 7.58 (d, J=8.1 Hz, 2H), 7.23-7.41 (m, 5H), 6.57 (s, 1H), 4.65-4.77(m, 1H), 4.35 (d, J=6 Hz, 2H), 2.90 (s, 3H), 1.53 (s, 9H).

Step d: N-((3′-Aminobiphenyl-4-yl)methyl)methanesulfonamide

A solution of [4′-(methanesulfonylamino-methyl)-biphenyl-3-yl]-carbamicacid tert-butyl ester (5 g, 13 mmol) in HCl/MeOH (4M, 150 mL) wasstirred at room temperature overnight. The mixture was concentrated todryness and the residue was washed with ether to give the targetcompound N-((3′-aminobiphenyl-4-yl)methyl)methanesulfonamide as its HClsalt (3.0 g, 71%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.54-7.71 (m, 6H), 7.46(d, J=7.8 Hz, 2H), 7.36 (d, J=7.5 Hz, 1H), 4.19 (s, 2H), 2.87 (s, 3H).MS (ESI) m/e (M+H⁺): 277.0.

Preparation 11:(R)-(1-(3′-Aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol (C-2)

Step a: (R)-Bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol

To a mixture of sat aq. NaHCO₃ (44 g, 0.53 mol), CH₂Cl₂ (400 mL) and(R)-pyrrolidin-2-yl-methanol (53 g, 0.53 mol) was added4-bromo-benzenesulfonyl chloride (130 g, 0.50 mol) in CH₂Cl₂ (100 mL).The reaction was stirred at 20° C. overnight. The organic phase wasseparated and dried over Na₂SO₄. Evaporation of the solvent underreduced pressure provided(R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (145 g,crude), which was used in the next step without further purification. ¹HNMR (CDCl₃, 300 MHz) δ 7.66-7.73 (m, 4H), 3.59-3.71 (m, 3H), 3.43-3.51(m, 1H), 3.18-3.26 (m, 1H), 1.680-1.88 (m, 3H), 1.45-1.53 (m, 1H).

Step b: (R)-(1-(3′-Aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol(C-2)

To a solution of(R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (1.6 g, 5.0mmol) in DMF (10 mL) was added 3-amino-phenyl boronic acid (0.75 g, 5.5mmol), Pd(PPh₃)₄ (45 mg, 0.15 mmol), potassium carbonate (0.75 g, 5.5mmol) and water (5 mL). The resulting mixture was degassed by gentlybubbling argon through the solution for 5 minutes at 20° C. The reactionmixture was then heated at 80° C. overnight. The reaction was filteredthrough a pad of silica gel, which was washed with CH₂Cl₂ (25 mL×3). Thecombined organics were concentrated under reduced pressure to give thecrude product, which was washed with EtOAc to give pure(R)-(1-(3′-aminobiphenyl-4-ylsulfonyl)pyrrolidin-2-yl)methanol (C-2)(810 mg, 49%). ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=8.7 Hz, 2H), 7.70(d, J=8.7 Hz, 2H), 7.23-7.28 (m, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.91 (d,J=1.8 Hz, 1H), 6.74 (dd, J=7.8, 1.2 Hz, 1H), 3.66-3.77 (m, 3H),3.45-3.53 (m, 1H), 3.26-3.34 (m, 1H), 1.68-1.88 (m, 3H), 1.45-1.55 (m,1H). MS (ESI) m/e (M+H⁺) 333.0.

Preparation 12: 3′-Amino-N-methylbiphenyl-4-sulfonamide (C-3)

Step a: 4-Bromo-N-methyl-benzenesulfonamide

To a mixture of sat aq. NaHCO₃ (42 g, 0.50 mol), CH₂Cl₂ (400 mL) andmethylamine (51.7 g, 0.50 mol, 30% in methanol) was added a solution of4-bromo-benzenesulfonyl chloride (130 g, 0.50 mol) in CH₂Cl₂ (100 mL).The reaction was stirred at 20° C. overnight. The organic phase wasseparated and dried over Na₂SO₄. Evaporation of the solvent underreduced pressure provided 4-bromo-N-methyl-benzenesulfonamide (121 g,crude), which was used in the next step without further purification. ¹HNMR (CDCl₃, 300 MHz) δ 7.65-7.74 (m, 4H), 4.40 (br, 1H), 2.67 (d, J=5.4Hz, 3H).

Step b: 3′-Amino-N-methylbiphenyl-4-sulfonamide (C-3)

To a solution of 4-bromo-N-methyl-benzene sulfonamide (2.49 g, 10 mmol)in DMF (20 mL) was added 3-amino-phenyl boronic acid (1.51 g, 11 mmol),Pd(PPh₃)₄ (90 mg, 0.30 mmol), potassium carbonate (1.52 g, 11 mmol) andwater (5 mL). The resulting mixture was degassed by gently bubblingargon through the solution for 5 minutes at 20° C. The reaction mixturewas then heated at 80° C. overnight. The reaction was filtered through apad of silica gel, which was washed with CH₂Cl₂ (50 mL×3). The combinedorganics were concentrated under reduced pressure to give crude product,which was washed with EtOAc to give pure3′-amino-N-methylbiphenyl-4-sulfonamide (C-3) (1.3 g, 50%). ¹H NMR (300MHz, CDCl₃) δ 7.85 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.19 (t,J=7.8 Hz, 1H), 6.95-7.01 (m, 2H), 6.73-6.77 (m, 1H), 2.54 (s, 3H). MS(ESI) m/e (M+H⁺) 263.0.

Preparation 13:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide

Step a:1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyclopropanecarboxamide

Methyl4-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-bromobenzoate(4.12 g, 9.9 mmol) was added to a solution of LiBH₄ (429 mg, 19.8 mmol)in THF/ether/H₂O (20/20/1 mL) and was allowed to stir at 25° C. After 16hours, the reaction was quenched with H₂O (10 mL). The reaction mixturewas diluted with dichloromethane (25 mL) and was extracted with 1N HCl(30 mL×3) and brine (30 mL). The organic extracts were dried over Na₂SO₄and evaporated. The crude product was purified by chromatography onsilica gel (eluting with 0-100% ethyl acetate in hexanes) to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyclopropanecarboxamide(2.84 g, 74%); ESI-MS m/z calc. 389.0, found 390.1 (M+1)⁺; retentiontime 2.91 minutes.

Step b:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)-phenyl)cyclopropanecarboxamide(39 mg, 0.10 mmol), 4-(dimethylcarbamoyl)-phenylboronic acid (29 mg,0.15 mmol), 1 M K₂CO₃ (0.3 mL, 0.3 mmol), Pd-FibreCat 1007 (8 mg, 0.1mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture washeated at 80° C. for 3 h. After cooling, the mixture was filtered andpurified by reverse phase HPLC to yield5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide(16 mg, 34%). ESI-MS m/z calc. 458.5, found 459.5 (M+1)⁺; Retention time2.71 minutes.

Preparation 14:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(ethoxymethyl)-N,N-dimethylbiphenyl-4-carboxamide

5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide(49 mg, 0.10 mmol) and para-toluenesulfonic acid (38 mg, 0.2 mmol) weredissolved in ethanol (1.0 mL) and irradiated in the microwave at 140° C.for 10 minutes. Volatiles were removed in vacuo and crude product waspurified by reverse phase HPLC to afford the pure product (6.4 mg, 13%).ESI-MS m/z calc. 486.2, found 487.5 (M+1)⁺; retention time 3.17 minutes.

Preparation 15:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-2′-(isopropoxymethyl)-N,N-dimethylbiphenyl-4-carboxamide

5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide(46 mg, 0.10 mmol) and para-toluenesulfonic acid (38 mg, 0.2 mmol) weredissolved in isopropanol (1.0 mL) and irradiated in the microwave at140° C. for 10 minutes. Volatiles were removed in vacuo and crudeproduct was purified by reverse phase HPLC to afford the pure product(22 mg, 44%). ESI-MS m/z calc. 500.2, found 501.3 (M+1)⁺; retention time3.30 minutes.

Preparation 16:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide

Step a:1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(hydroxymethyl)phenyl)cyclopropane-carboxamide(1.08 g, 2.78 mmol), methanesulfonyl chloride (0.24 mL, 3.1 mmol), andN,N-diisopropylethylamine (0.72 mL, 4.1 mmol) were dissolved inacetonitrile (27 mL) at 25° C. After complete dissolution, KCN (450 mg,6.95 mmol) was added and the reaction was stirred for 14 d. The reactionwas diluted with dichloromethane (25 mL) and washed with water (25 mL).The organic extracts were dried over Na₂SO₄ and evaporated. The crudeproduct was purified by chromatography on silica gel (eluting with0-100% ethyl acetate in hexanes) to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclopropanecarboxamide (514 mg, 46%). ESI-MS m/z calc. 398.0, found 399.1 (M+1)⁺;retention time 3.24 minutes.

Step b:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclopropane-carboxamide(40 mg, 0.10 mmol), 4-(dimethylcarbamoyl)phenylboronic acid (29 mg, 0.15mmol), 1 M K₂CO₃ (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol),and N,N-dimethylformamide (1 mL) were combined. The mixture wasirradiated in the microwave at 150° C. for 10 minutes. Volatiles wereremoved in vacuo and crude product was purified by chromatography onsilica gel (eluting with 0-100% ethyl acetate in hexanes) to afford5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide(9.1 mg, 20%). ESI-MS m/z calc. 467.2, found 468.5 (M+1)⁺; retentiontime 2.96 minutes.

Preparation 17:2′-((1H-Tetrazol-5-yl)methyl)-5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N-dimethylbiphenyl-4-carboxamide

5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide(32 mg, 0.070 mmol), sodium azide (55 mg, 0.84 mmol), and ammoniumchloride (45 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (1.5mL) and irradiated in the microwave at 100° C. for 2 hours. Aftercooling, the mixture was filtered and purified by reverse phase HPLC toyield2′-((1H-tetrazol-5-yl)methyl)-5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N-dimethylbiphenyl-4-carboxamide (9.2 mg, 26%). ESI-MSm/z calc. 510.2, found 511.5 (M+1)⁺; Retention time 2.68 minutes.

Preparation 18:2′-(2-Amino-2-oxoethyl)-5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N-dimethylbiphenyl-4-carboxamide

5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide(58 mg, 0.12 mmol), H₂O₂ (30 wt % solution in water, 36 μL, 1.2 mmol),and NaOH (10 wt % in water, 0.15 mL, 0.42 mmol) were dissolved in MeOH(1.2 mL) and stirred at 25° C. for 2 hours. The reaction was filteredand purified by reverse phase HPLC to yield2′-(2-amino-2-oxoethyl)-5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N-dimethylbiphenyl-4-carboxamide(14 mg, 23%). ESI-MS m/z calc. 485.2, found 486.5 (M+1)⁺; Retention time2.54 minutes.

Preparation 19:N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide(37 mg, 0.10 mmol), 4-((tert-butoxycarbonylamino)methyl)phenylboronicacid (37 mg, 0.15 mmol), 1 M K₂CO₃ (0.2 mL, 0.2 mmol), Pd-FibreCat 1007(8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. Themixture was irradiated in the microwave at 150° C. for 10 minutes. Thereaction was filtered and purified by reverse phase HPLC. The obtainedmaterial was dissolved in dichloromethane (2 mL) containingtrifluoroacetic acid (2 mL) and stirred at 25° C. for 1 hour. Thereaction was filtered and purified by reverse phase HPLC to yieldN-(4′-(aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamideas the TFA salt (8.1 mg, 20%). ESI-MS m/z calc. 400.2, found 401.5(M+1)⁺; retention time 2.55 minutes.

Preparation 20:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propionamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide

N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(40 mg, 0.10 mmol), propionyl chloride (8.7 μL, 0.10 mmol) and Et₃N (28μL, 0.20 mmol) were dissolved in dichloromethane (1.0 mL) and allowed tostir at 25° C. for 3 hours. Volatiles were removed in vacuo and crudeproduct was purified by reverse phase HPLC to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propionamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide(13 mg, 28%). ESI-MS m/z calc. 456.5, found 457.5 (M+1)⁺; retention time3.22 minutes.

Preparation 21:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propylsulfonamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide

N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(40 mg, 0.10 mmol), 1-propanesulfonyl chloride (11 μL, 0.10 mmol) andEt₃N (28 μL, 0.20 mmol) were dissolved in dichloromethane (1.0 mL) andallowed to stir at 25° C. for 16 hours. Volatiles were removed in vacuoand crude product was purified by reverse phase HPLC to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propylsulfonamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide(5.3 mg, 10%). ESI-MS m/z calc. 506.6, found 507.3 (M+1)⁺; retentiontime 3.48 minutes.

Preparation 22:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((propylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide

N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(40 mg, 0.10 mmol), propionaldehyde (5.1 μL, 0.10 mmol) and Ti(OPr)₄ (82μL, 0.30 mmol) were dissolved in dichloromethane (1.0 mL) and mono-glyme(1.0 mL). The mixture was allowed to stir at 25° C. for 16 hours. NaBH₄(5.7 mg, 0.15 mmol) was added and the reaction was stirred for anadditional 1 h. The reaction was diluted to 5 mL with dichloromethanebefore water (5 mL) was added. The reaction was filtered through celiteto remove the titanium salts and the layers separated. The organicextracts were dried over Na₂SO₄ and evaporated. The crude product waspurified by reverse phase HPLC to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((propylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide(7.8 mg, 14%). ESI-MS m/z calc. 442.6, found 443.5 (M+1)⁺; retentiontime 2.54 minutes.

Preparation 23:1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-((isopentylamino)methyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide

N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(40 mg, 0.10 mmol), 3-methylbutanal (8.6 mg, 0.10 mmol) and Ti(OPr)₄ (82μL, 0.30 mmol) were dissolved in dichloromethane (1.0 mL) and mono-glyme(1.0 mL) and allowed to stir at 25° C. for 16 hours. NaBH₄ (5.7 mg, 0.15mmol) was added and the reaction was stirred for an additional 1 h. Thereaction was diluted to 5 mL with dichloromethane before water (5 mL)was added. The reaction was filtered through celite to remove thetitanium salts and the layers separated. The organic extracts were driedover Na₂SO₄ and evaporated. The crude product was purified by reversephase HPLC to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-((isopentylamino)methyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide(5.7 mg, 10%). ESI-MS m/z calc. 470.3, found 471.5 (M+1)⁺; retentiontime 2.76 minutes.

Preparation 24:1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide(3.0 g, 8.1 mmol), 4-(hydroxymethyl)phenylboronic acid (1.5 g, 9.7mmol), 1 M K₂CO₃ (16 mL, 16 mmol), Pd-FibreCat 1007 (640 mg), andN,N-dimethylformamide (80 mL) were combined. The mixture was heated at80° C. for 3 h. The volatiles were removed in vacuo and residue wasredissolved in dichloromethane (100 mL). The organics were washed with1N HCl (100 mL×2), then dried over Na₂SO₄ and evaporated. The crudeproduct was purified by chromatography on silica gel to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide(1.9 g, 59%). ESI-MS m/z calc. 401.5, found 402.5 (M+1)⁺; retention time3.18 minutes.

Preparation 25:1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(methoxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide(40 mg, 0.10 mmol), para-toluenesulfonic acid (24 mg, 0.13 mmol) andMeOH (53 μL, 1.3 mmol) were dissolved in toluene (2.0 mL) and irradiatedin the microwave at 140° C. for 10 minutes. Volatiles were removed invacuo and crude product was purified by reverse phase HPLC to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-(methoxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide(9.6 mg, 23%). ESI-MS m/z calc. 415.5, found 416.5 (M+1)⁺; retentiontime 3.68 minutes.

Preparation 26:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide(610 mg, 1.52 mmol), methanesulfonyl chloride (0.13 mL, 1.7 mmol), andN,N-diisopropylethylamine (0.79 mL, 4.6 mmol) were dissolved indichloromethane (10 mL) at 25° C. The reaction was stirred for 10minutes before a 2.0 M solution of MeNH₂ in THF (15 mL, 30 mmol) wasadded. The mixture was stirred for 30 minutes at ambient temperaturebefore it was extracted with 1N HCl (20 mL×2) and saturated NaHCO₃ (20mL×2). The organic extracts were dried over Na₂SO₄ and evaporated. Thecrude product was purified by chromatography on silica gel (eluting with0-20% methanol in dichloromethane) to afford1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide(379 mg, 60%). ESI-MS m/z calc. 414.5, found 415.5 (M+1)⁺; retentiontime 2.44 minutes.

Preparation 27:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((N-methylpivalamido)methyl)biphenyl-3-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide(30 mg, 0.070 mmol), pivaloyl chloride (12.3 μL, 0.090 mmol) and Et₃N(20 μL, 0.14 mmol) were dissolved in N,N-dimethylformamide (1.0 mL) andallowed to stir at 25° C. for 3 hours. The crude reaction was purifiedby reverse phase HPLC to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((N-methylpivalamido)methyl)biphenyl-3-yl)cyclopropanecarboxamide(15 mg, 30%). ESI-MS m/z calc. 498.3, found 499.3 (M+1)⁺; retention time3.75 minutes.

Preparation 28:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((N-methylmethylsulfonamido)methyl)biphenyl-3-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)-methyl)biphenyl-3-yl)cyclopropanecarboxamide (30 mg, 0.070 mmol), methanesulfonyl chloride (7.8 μL, 0.14mmol) and Et₃N (30 μL, 0.22 mmol) were dissolved inN,N-dimethylformamide (1.0 mL) and allowed to stir at 25° C. for 16hours. The crude reaction was purified by reverse phase HPLC to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((N-methylmethylsulfonamido)methyl)biphenyl-3-yl)cyclopropanecarboxamide (22 mg, 64%). ESI-MS m/zcalc. 492.2, found 493.3 (M+1)⁺; retention time 3.45 minutes.

Preparation 29:1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-((isobutyl(methyl)amino)-methyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide(49 mg, 0.12 mmol), isobutyraldehyde (11 μL, 0.12 mmol) and NaBH(OAc)₃(76 mg, 0.36 mmol) were dissolved in dichloroethane (2.0 mL) and heatedat 70° C. for 16 hours. The reaction was quenched with MeOH (0.5 mL) and1 N HCl (0.5 mL). The volatiles were removed in vacuo and the crudeproduct was purified by reverse phase HPLC to afford1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-((isobutyl(methyl)amino)-methyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamideas the TFA salt (5.0 mg, 9%). ESI-MS m/z calc. 470.3, found 471.3(M+1)⁺; retention time 2.64 minutes.

The following compounds were prepared using procedures 20-23 and 27-29above: 6, 14, 24, 26, 70, 79, 84, 96, 114, 122, 159, 200, 206, 214, 223,248, 284-5, 348, 355, 382, 389, 391, 447, 471, 505, 511, 524, 529-30,534, 551, 562, 661, 682, 709, 783, 786, 801, 809, 828, 844, 846, 877,937, 947, 1012, 1049, 1089.

Preparation 30:1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)cyclopropane-carboxamide

4-(2-Methylthiazol-4-yl)aniline (19 mg, 0.10 mmol) and1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100mmol) were dissolved in acetonitrile (1.0 mL) containing triethylamine(42 μL, 0.30 mmol).O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and theresulting solution was allowed to stir for 16 hours. The crude productwas purified by reverse-phase preparative liquid chromatography to yield1-(benzo[d][1,3]dioxol-5-yl)-N-(4-(2-methylthiazol-4-yl)phenyl)cyclopropane-carboxamide.ESI-MS m/z calc. 378.1, found; 379.1 (M+1)⁺; Retention time 2.72minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 1.04-1.10 (m, 2H), 1.40-1.44 (m,2H), 2.70 (s, 3H), 6.03 (s, 2H), 6.88-6.96 (m, 2H), 7.01 (d, J=1.4 Hz,1H), 7.57-7.61 (m, 2H), 7.81-7.84 (m, 3H), 8.87 (s, 1H).

Preparation 31:1-Benzo[1,3]dioxol-5-yl-N-[3-[4-(methylsulfamoyl)phenyl]phenyl]-cyclopropane-1-carboxamide

To a solution of 1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl chloride(0.97 mmol) in CH₂Cl₂ (3 mL) at ambient temperature was added a solutionof 3′-amino-N-methylbiphenyl-4-sulfonamide (0.25 g, 0.97 mmol), Et₃N(0.68 mL, 4.9 mmol), DMAP (0.050 g, 0.058 mmol), and CH₂Cl₂ (1 mL)dropwise. The mixture was allowed to stir for 16 h before it was dilutedwith CH₂Cl₂ (50 mL). The solution was washed with 1N HCl (2×25 mL), sat.aq. NaHCO₃ (2×25 mL), then brine (25 mL). The organics were dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography (5-25% EtOAc/hexanes) to provide1-benzo[1,3]dioxol-5-yl-N-[3-[4-(methylsulfamoyl)phenyl]phenyl]-cyclopropane-1-carboxamideas a white solid. ESI-MS m/z calc. 450.5, found 451.3 (M+1)⁺. Retentiontime of 3.13 minutes.

The following compounds were prepared using procedures 30 and 31 above:4-5, 27, 35, 39, 51, 55, 75, 81, 90, 97-8, 101, 110, 132, 146, 155, 166,186, 208, 211, 218, 230, 239, 245, 247, 258, 261, 283, 292, 308, 334,339, 352, 356, 379, 405, 411, 433, 462, 477, 504, 514, 526, 536, 554,563, 573, 590-2, 612, 619, 623, 627, 637, 648, 653, 660, 668-9, 692,728, 740, 747, 748, 782, 814, 826-7, 834-6, 845, 916, 931-2, 938, 944,950, 969, 975, 996, 1004, 1007, 1009, 1033, 1064, 1084-5, 1088, 1097,1102, 1127, 1151, 1157, 1159, 1162, 1186, 1193.

Preparation 32:4-[5-(1-Benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]benzoicacid

1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide(B-8) (5.1 g, 14 mmol), 4-boronobenzoic acid (3.4 g, 20 mmol), 1 M K₂CO₃(54 mL, 54 mmol), Pd-FibreCat 1007 (810 mg, 1.35 mmol), and DMF (135 mL)were combined. The mixture was heated at 80° C. for 3 h. After cooling,the mixture was filtered and DMF was removed in vacuo. The residue waspartitioned between dichloromethane (250 mL) and 1N HCl (250 mL). Theorganics were separated, washed with saturated NaCl solution (250 mL),and dried over Na₂SO₄. Evaporation of organics yielded4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]benzoicacid (5.5 g, 98%). ESI-MS m/z calc. 415.1, found 416.5 (M+1)⁺; Retentiontime 3.19 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.83 (s,1H), 8.06-8.04 (m, 2H), 7.58-7.56 (m, 1H), 7.50-7.48 (m, 3H), 7.27-7.24(m, 1H), 7.05-7.04 (m, 1H), 6.98-6.94 (m, 2H), 6.07 (s, 2H), 2.22 (s,3H), 1.46-1.44 (m, 2H), 1.12-1.09 (m, 2H).

Preparation 33:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methyl-N-(2-(pyridin-2-yl)ethyl)biphenyl-4-carboxamide

2-(Pyridin-2-yl)ethanamine (12 mg, 0.10 mmol) and5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-4-carboxylicacid (42 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1.0 mL)containing triethylamine (28 μL, 0.20 mmol).O-(7-Azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and theresulting solution was allowed to stir for 1 hour at ambienttemperature. The crude product was purified by reverse-phase preparativeliquid chromatography to yield5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methyl-N-(2-(pyridin-2-yl)ethyl)biphenyl-4-carboxamideas the trifluoroacetic acid salt (43 mg, 67%). ESI-MS m/z calc. 519.2,found 520.5 (M+1)⁺; Retention time 2.41 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 8.77 (s, 1H), 8.75-8.74 (m, 1H), 8.68-8.65 (m, 1H), 8.23 (m,1H), 7.83-7.82 (m, 2H), 7.75-7.68 (m, 2H), 7.48-7.37 (m, 4H), 7.20-7.18(m, 1H), 6.99-6.98 (m, 1H), 6.90-6.89 (m, 2H), 6.01 (s, 2H), 3.72-3.67(m, 2H), 3.20-3.17 (m, 2H), 2.15 (s, 3H), 1.40-1.37 (m, 2H), 1.06-1.03(m, 2H).

The following compounds were prepared using procedure 33 above: 32, 78,118, 134, 156, 171, 188, 237, 279, 291, 297, 309, 319, 338, 341, 362,373, 376, 393, 406-7, 410, 448, 452-3, 474, 482, 494, 508, 577, 580,593-4, 622, 629, 638, 651, 663-4, 681, 698, 704, 707, 710, 736-7, 739,775, 806, 810, 825, 842, 853, 866, 871, 900, 905-7, 926, 935, 941, 966,971, 973, 978-9, 1046, 1048, 1066, 1077, 1079, 1083, 1141, 1150, 1155-6,1163, 1180, 1185, 1187, 1198, 1201.

Preparation 34:4-[5-(1-Benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]-N,N-dimethyl-benzamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide(0.10 mmol),N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(0.11 mmol), K₂CO₃ (240 μL, 1M), Pd-FibreCat (7 mg), and DMF (1 mL) werecombined. The mixture was heated at 150° C. for 5 min (5 min ramp time)in a microwave reactor. After cooling, the mixture was filtered andpurified by prep-HPLC to provide4-[5-(1-benzo[1,3]dioxol-5-ylcyclopropyl)carbonylamino-2-methyl-phenyl]-N,N-dimethyl-benzamide.ESI-MS m/z calc. 442.2, found 443.5 (M+1)⁺; Retention time 3.12 minutes.¹H NMR (400 MHz, DMSO-d₆) δ 1.02-1.08 (m, 2H), 1.37-1.44 (m, 2H), 2.17(s, 3H), 2.96 (s, 3H), 3.00 (s, 3H), 6.01 (s, 2H), 6.87-6.93 (m, 2H),6.98 (d, J=1.3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.34-7.37 (m, 2H),7.40-7.52 (m, 4H), 8.75 (s, 1H).

Preparation 35:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(isopropoxymethyl)-N,N-dimethylbiphenyl-4-carboxamide

Sodium hydride (2.2 mg, 0.055 mmol, 60% by weight dispersion in oil) wasslowly added to a stirred solution of5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N,2′-trimethylbiphenyl-4-carboxamide(21 mg, 0.048 mmol) in a mixture of 0.90 mL of anhydrous tetrahydrofuran(THF) and 0.10 mL of anhydrous N,N-dimethylformamide (DMF). Theresulting suspension was allowed to stir for 3 minutes beforeiodomethane (0.0048 mL, 0.072 mmol) was added to the reaction mixture.An additional aliquot of sodium hydride and iodomethane were required toconsume all of the starting material which was monitored by LCMS. Thecrude reaction product was evaporated to dryness, redissolved in aminimum of DMF and purified by preparative LCMS chromatography to yield5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(isopropoxymethyl)-N,N-dimethylbiphenyl-4-carboxamide(9.1 mg, 42%) ESI-MS m/z calc. 456.2, found 457.5 (M+1)⁺. Retention timeof 2.94 minutes. ¹H NMR (400 MHz, CD₃CN) δ 0.91-0.93 (m, 2H), 1.41-1.45(m, 2H), 2.23 (s, 3H), 3.00 (s, 3H), 3.07 (s, 3H), 3.20 (s, 3H), 5.81(s, 2H), 6.29-6.36 (m, 2H), 6.56 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 6.92(dd, J=1.6, 7.9 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H),7.46 (dd, J=1.8, 6.4 Hz, 2H).

Preparation 36:(S)-1-(5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-4-ylsulfonyl)pyrrolidine-2-carboxylicacid

Step a: 4-(4,4′-Dimethoxybenzhydryl)-thiophenyl boronic acid

4,4′-Dimethoxybenzhydrol (2.7 g, 11 mmol) and 4-mercaptophenylboronicacid (1.54 g, 10 mmol) were dissolved in AcOH (20 mL) and heated at 60°C. for 1 h. Solvent was evaporated and the residue was dried under highvacuum. This material was used without further purification.

Step b:4′-[Bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamine

4-(4,4′-Dimethoxybenzhydryl)-thiophenyl boronic acid (10 mmol) and3-bromo-4-methylaniline (1.86 g, 10 mmol) were dissolved in MeCN (40mL). Pd (PPh₃)₄ (˜50 mg) and aqueous solution K₂CO₃ (1M, 22 mL) wereadded before the reaction mixture was heated portion-wise in a microwaveoven (160° C., 400 sec). Products were distributed between ethyl acetateand water. The organic layer was washed with water, brine and dried overMgSO₄. Evaporation yielded an oil that was used without purification inthe next step. ESI-MS m/z calc. 441.0, found 442.1 (M+1).

Step c: 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid4′-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide

4′-[Bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamine(˜10 mmol) and 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.28g, 11 mmol) were dissolved in chloroform (25 mL) followed by addition ofTCPH (4.1 g, 12 mmol) and DIEA (5.0 mL, 30 mmol). The reaction mixturewas heated at 65° C. for 48 h. The volatiles were removed under reducedpressure. The residue was distributed between water (200 mL) and ethylacetate (150 mL). The organic layer was washed with 5% NaHCO₃ (2×150mL), water (1×150 mL), brine (1×150 mL) and dried over MgSO₄.Evaporation of the solvent yielded crude1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid4′-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide asa pale oil, which was used without further purification. ESI-MS m/zcalc. 629.0, found 630.0 (M+1) (HPLC purity ˜85-90%, UV254 nm).

Step d:5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methylbiphenyl-4-sulfonicacid

1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid4′-[bis-(4-methoxyphenyl)-methylsulfanyl]-6-methylbiphenyl-3-ylamide(˜8.5 mmol) was dissolved in acetic acid (75 mL) followed by addition of30% H₂O₂ (10 mL). Additional hydrogen peroxide (10 mL) was added 2 hlater. The reaction mixture was stirred at 35-45° C. overnight (˜90%conversion, HPLC). The volume of reaction mixture was reduced to a thirdby evaporation (bath temperature below 40° C.). The reaction mixture wasloaded directly onto a prep RP HPLC column (C-18) and purified. Theappropriate fractions with were collected and evaporated to provide5′-[(1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methylbiphenyl-4-sulfonicacid (2.1 g, 46%, cal. based on 4-mercaptophenylboronic acid). ESI-MSm/z calc. 451.0, found 452.2 (M+1).

Step e:5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methylbiphenyl-4-sulfonylchloride

5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methylbiphenyl-4-sulfonicacid (1.9 g, 4.3 mmol) was dissolved in POCl₃ (30 mL) followed by theaddition of SOCl₂ (3 mL) and DMF (100 μl). The reaction mixture washeated at 70-80° C. for 15 min. The reagents were evaporated andre-evaporated with chloroform-toluene. The residual brown oil wasdiluted with chloroform (22 mL) and immediately used for sulfonylation.ESI-MS m/z calc. 469.0, found 470.1 (M+1).

Step f:(S)-1-{5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropane-carbonyl)-amino]-2′-methyl-biphenyl-4-sulfonyl}-pyrrolidine-2-carboxylicacid

L-Proline (57 mg, 0.50 mmol) was treated withN,O-bis(trimethylsilyl)acetamide (250 μl, 1.0 mmol) in 1 mL dioxaneovernight at 50° C. To this mixture was added5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-4-sulfonylchloride (˜35 μmol, 400 μl solution in chloroform) followed by DIEA (100μL). The reaction mixture was kept at room temperature for 1 h,evaporated, and diluted with DMSO (400 μl). The resulting solution wassubjected to preparative HPLC purification. Fractions containing thedesired material were combined and concentrated in vacuum centrifuge at40° C. to provide the trifluoroacetic salt of(S)-1-{5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methyl-biphenyl-4-sulfonyl}-pyrrolidine-2-carboxylicacid. ESI-MS m/z calc. 548.1, found 549.1 (M+1), retention time 3.40min; ¹H NMR (250 MHz, DMSO-d₆) δ 1.04 (m. 2H), δ 1.38 (m, 2H), δ 1.60(m, 1H), δ 1.80-1.97 (m, 3H) δ 2.16 (s, 3H), δ 3.21 (m, 1H), 3.39 (m,1H), 4.15 (dd, 1H, J=4.1 Hz, J=7.8 Hz), δ 6.01 (s, 2H), δ 6.89 (s, 2H),δ 6.98 (s, 1H), δ 7.21 (d, 1H, J=8.3 Hz), δ 7.45 (d, 1H, J=2 Hz), δ 7.52(dd, 1H, J=2 Hz, J=8.3 Hz), δ 7.55 (d, 2H, J=8.3 Hz), δ 7.88 (d, 2H,J=8.3 Hz), δ 8.80 (s, 1H).

The following compounds were prepared using procedure 36 above: 9, 17,30, 37, 41, 62, 88, 104, 130, 136, 169, 173, 184, 191, 216, 219, 259-60,265, 275, 278, 281, 302, 306, 342, 350, 366, 371, 380, 387, 396, 404,412, 430, 438, 449, 460, 478, 486, 496, 499-500, 503, 512, 517, 579,581-2, 603, 610, 611, 615, 652, 676, 688, 701, 706, 712, 725, 727, 732,734, 751, 764, 770, 778, 780, 790, 802, 829, 841, 854, 885, 889, 897,902, 930, 951-2, 970, 986, 992, 994, 997, 1040, 1050-1, 1054, 1056,1065, 1082, 1090, 1093, 1107, 1114, 1130, 1143, 1147, 1158, 1160, 1164,1170, 1174-5.

Preparation 37:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-fluoro-2′-methylbiphenyl-4-carboxamide

Step a:1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide(5.0 g, 13 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.1 g, 16mmol), Pd(dppf)Cl₂ (0.66 g, 0.81 mmol), and DMF (100 mL) were added to aflask containing oven-dried KOAc (3.9 g, 40 mmol). The mixture washeated at 80° C. for 2 h (˜40% conversion). The mixture was cooled toambient temperature and the volatiles were removed under vacuum. Theresidue was taken up in CH₂Cl₂, filtered, and loaded onto a SiO₂ column(750 g of SiO₂). The product was eluted with EtOAc/Hexanes (0-25%, 70min, 250 mL/min) to provide1-(benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide(1.5 g, 27%) and unreacted starting material:1-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide(3.0 g).

Step b:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-fluoro-2′-methylbiphenyl-4-carboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide(42 mg, 0.10 mmol), 4-bromo-3-fluorobenzamide (24 mg, 0.11 mmol),Pd-FibreCat 1007 (10 mg), K₂CO₃ (1M, 240 mL), and DMF (1 mL) werecombined in a scintillation vial and heated at 80° C. for 3 hr. Themixture was filtered and purified using reverse-phase preparative HPLCto provide5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-fluoro-2′-methylbiphenyl-4-carboxamide(ESI-MS m/z calc. 428.5, found 429.5 (M+1); retention time 3.30 min).

Preparation 38:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-3′-(2H-tetrazol-5-yl)biphenyl-3-yl)cyclopropanecarboxamide

Step a:1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide

To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid(1.74 g, 8.57 mmol) in DMF (10 mL) was added HATU (3.59 g, 9.45 mmol),Et₃N (3.60 mL, 25.8 mmol), then4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.19 g,9.40 mmol) at ambient temperature. The mixture was heated at 70° C. for18 h. The mixture was cooled, then concentrated under reduced pressure.The residue was taken up in EtOAc before it was washed with H₂O, thenbrine (2×). The organics were dried (Na₂SO₄) and concentrated underreduced pressure to provide an orange-tan foam/semi-solid. Columnchromatography on the residue (5-15% EtOAc/hexanes) provided a whitefoam. MeOH was added to the material and the slurry was concentratedunder reduced pressure to yield 3.10 g of1-(benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamideas a white, granular solid, (85%).

Step b:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-3′-(2H-tetrazol-5-yl)-biphenyl-3-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide(42.1 mg, 0.100 mmol), 5-(3-bromophenyl)-tetrazole (22.5 mg, 0.100mmol), a 1 M aqueous solution of potassium carbonate (0.50 mL),Pd-FibreCat 1007 (6 mg), and ethanol (0.50 mL) were combined. Themixture was heated at 110° C. for 5 min (5 min ramp time) in a microwavereactor. After cooling, the mixture was filtered and purified byprep-HPLC to provide1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-3′-(2H-tetrazol-5-yl)-biphenyl-3-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 439.2, found 440.2 (M+1)⁺; Retention time 2.59 minutes.

The following compounds were prepared using procedures 13, 24, 32, 34,37 and 38 above: 1-3, 7-8, 10-13, 15-6, 18-23, 25, 28-9, 31, 33-4, 36,38, 40, 42-50, 52-54, 56-61, 63-9, 71, 72(1), 73-4, 76-7, 80, 82-3,85-7, 89, 91-5, 99-100, 102-3, 105-9, 111-113, 115(1), 116-7, 119-21,123-4, 125(2), 126-9, 131, 133, 135, 137-45, 147-54, 157-8, 160-5,167-8, 170, 172, 174-5, 176(1), 177-83, 185, 187, 189-90, 193-4, 195(1),196, 197(1), 198-9, 201-5, 207, 209-10, 212-3, 215, 217, 220-2, 224-9,231, 232(2), 233-6, 238, 240-4, 246, 249-52, 253(1), 254-7, 262-74,276-7, 280, 282, 286-8, 290, 293-6, 298-301, 303-5, 307, 310, 312-8,320-31, 332(2), 333, 335-7, 340, 340, 343-7, 349, 351, 353-4, 357-61,363-4, 367-70, 372, 374, 375(2), 377(2), 378, 381, 383-6, 388, 390,394-5, 397-403, 408, 409(2), 413, 414(1), 415-29, 431-2, 434-7, 439-46,450-1, 454-8, 461, 463-4, 466-8, 469(2), 470, 472-3, 475-6, 479, 480-1,483-5, 487-93, 497-8, 501-2, 506-7, 509-510, 513, 515-6, 518-21, 523,525, 527-8, 531-3, 535, 537-8, 539(1), 540-50, 552-3, 555-561, 564-72,574-6, 578, 583-89, 595-602, 604-5, 606(1), 607-9, 613-4, 616-8, 620,624-6, 630, 631(1), 632-6, 639-42, 644-7, 649-50, 654-9, 662, 665-7,670-1, 673-5, 677-80, 683-5, 686(1), 687, 689-91, 693-97, 699-700,702-3, 705, 708, 711, 713-24, 726, 729(2), 730, 733, 735(1), 738, 741-6,752-4, 756-63, 765-9, 771-4, 776-7, 779, 781, 784-5, 787-9, 791-6,798-799, 800(1), 803-5, 807-8, 811, 813, 815-21, 822(1), 823-4, 830-3,837-40, 847-52, 855-65, 867-70, 872-76, 878-84, 886-8, 890-6, 898-9,901, 903-4, 908, 910-4, 915(1), 917-25, 927-8, 933-4, 936, 939-40,942-3, 945-6, 948-9, 953-64, 967-8, 972, 974, 976-7, 980-5, 987-91, 993,995, 998-1001, 1003, 1005-6, 1008, 1010-11, 1013-32, 1034-6, 1038-9,1041-5, 1047, 1052-3, 1055, 1057-60, 1062-3, 1067-9, 1071-6, 1078, 1081,1086-7, 1091-2, 1094-6, 1098-1101, 1103-6, 1108-13, 1115, 1116(2),1117-26, 1128-9, 1131-40, 1142, 1144-6, 1148-9, 1152-4, 1161, 1165,1167-9, 1171-3, 1176, 1177(1), 1178-9, 1181-4, 1188-92, 1194, 1197,1199-1200, 1202-4, 1205(2).

⁽¹⁾ Following the coupling with2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoindoline-1,3-dioneand2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoindoline-1,3-dione,examples were obtained after removal of the phthalimide group withhydrazine using known deprotecting procedures.

⁽²⁾ Following the coupling with4-((tert-butoxycarbonylamino)methyl)phenylboronic acid, examples wereobtained after removal of the Boc-group with TFA using knowndeprotecting procedures.

Preparation 39:5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide

Step a:5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)biphenyl-2-carboxylicacid

Methyl5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)biphenyl-2-carboxylate(84 mg, 0.20 mmol) was dissolved in DMF (2.0 mL) with 1M K₂CO₃ (1.0 mL)and irradiated in the microwave at 150° C. for 10 minutes. Purificationby reverse phase HPLC yielded5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)-biphenyl-2-carboxylicacid (7.3 mg, 8%). ESI-MS m/z calc. 472.5, found 473.3 (M+1)⁺; retentiontime 2.79 minutes.

Step b:5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide

5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)biphenyl-2-carboxylic acid (47 mg, 0.10 mmol) and 75 μL of a 2.0 Msolution of methylamine in tetrahydrofuran (0.15 mmol) were dissolved inDMF (1.0 mL) containing Et₃N (28 μL, 0.20 mmol).O-(7-Azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluroniumhexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and theresulting solution was allowed to stir for 3 hours. The mixture wasfiltered and purified by reverse phase HPLC to yield5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide(5.0 mg, 10%). ESI-MS m/z calc. 485.5, found 486.5 (M+1)⁺; retentiontime 2.54 minutes.

The following compounds were prepared using procedure 39 above: 311,495, 755, 812, 1070.

Preparation 40:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-((2-hydroxyethylamino)methyl)-N,N-dimethylbiphenyl-4-carboxamide

To a solution of5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(hydroxymethyl)-N,N-dimethylbiphenyl-4-carboxamide(46 mg, 0.10 mmol) and diisopropylethylamine (30 μL, 0.20 mmol) in DMF(1.0 mL) was added methanesulfonyl chloride (8.5 μL, 0.11 mmol). Afterstirring at 25° C. for 15 minutes, ethanolamine (13 μL, 0.30 mmol) wasadded and the mixture was stirring for an additional 1 hour. The mixturewas filtered and purified by reverse phase HPLC to yield5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-((2-hydroxyethyl-amino)methyl)-N,N-dimethylbiphenyl-4-carboxamideas the trifluoroacetic acid salt (5.0 mg, 8%). ESI-MS m/z calc. 501.2,found 502.5 (M+1)⁺; retention time 2.28 minutes.

The following compounds were prepared using procedure 40 above: 843,909, 1080.

Preparation 41:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-((2-hydroxyethylamino)methyl)-N,N-dimethylbiphenyl-4-carboxamide

Step a: 4-Bromo-2-fluoro-N,N-dimethylbenzenesulfonamide

To 4-bromo-2-fluorobenzene-1-sulfonyl chloride (1.0 g, 3.7 mmol) andEt₃N (1.5 mL, 11 mmol) in dichloromethane (10 mL) was added a solutionof dimethylamine 2.0 M in THF (2.2 mL, 4.4 mmol). The reaction wasstirred at ambient temperature for 30 minutes. The reaction was washedwith 10 mL of 1N aqueous HCl and 10 mL of brine. Organics were driedover Na₂SO₄ and evaporated to dryness. Crude product was purified bychromatography on silica gel (eluting with 0-25% ethyl acetate inhexanes) to afford 4-bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (780mg, 75%).

Step b: 4-Bromo-2-cyano-N,N-dimethylbenzenesulfonamide

4-Bromo-2-fluoro-N,N-dimethylbenzenesulfonamide (1.0 g, 3.5 mmol) andsodium cyanide (350 mg, 7.1 mmol) were dissolved in DMF (3 mL) andirradiated in the microwave at 150° C. for 20 minutes. DMF was removedin vacuo and the residue was redissolved in dichloromethane (5 mL). Theorganics were washed with 5 mL of each 1N aqueous HCl, saturated aqueousNaHCO₃, and brine. Organics were dried over Na₂SO₄ and evaporated todryness. Crude product was purified by chromatography on silica gel(eluting with 0-50% ethyl acetate in hexanes) to afford4-bromo-2-cyano-N,N-dimethylbenzenesulfonamide (72 mg, 7%). ESI-MS m/zcalc. 288.0, found 288.9 (M+1)⁺; retention time 1.44 minutes.

Step c: 5-Bromo-2-(N,N-dimethylsulfamoyl)benzoic acid

A mixture of 4-bromo-2-cyano-N,N-dimethylbenzenesulfonamide (110 mg,0.38 mmol) and 1N aqueous NaOH (2.0 mL, 2.0 mmol) in 1,4-dioxane (2 mL)was heated at reflux. The cooled reaction mixture was washed withdichloromethane (5 mL). The aqueous layer was acidified by the additionof 1N aqueous HCl. The acidified aqueous layer was extracted withdichloromethane (2×5 mL). The combined organics were dried over Na₂SO₄and evaporated to dryness to yield5-bromo-2-(N,N-dimethylsulfamoyl)benzoic acid in 34% yield (40 mg, 0.13mmol). ESI-MS m/z calc. 307.0, found 308.1 (M+1)⁺; retention time 1.13minutes.

Step d:5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4-(N,N-dimethylsulfamoyl)-2′-methylbiphenyl-3-carboxylicacid

1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide(42 mg, 0.10 mmol), 5-bromo-2-(N,N-dimethylsulfamoyl)benzoic acid (31mg, 0.10 mmol), 1 M K₂CO₃ (0.30 mL, 0.30 mmol), and Pd-FibreCat 1007 (8mg, 0.004 mmol) were dissolved in DMF (1 mL) and heated at 80° C. for 3hr in an oil bath. The mixture was filtered and purified by reversephase HPLC to yield5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4-(N,N-dimethylsulfamoyl)-2′-methylbiphenyl-3-carboxylicacid. ESI-MS m/z calc. 522.6, found 523.5 (M+1)⁺; retention time 1.79minutes.

Preparation 42: 3-Bromo-4-(3-methyloxetan-3-yl)aniline

Step a: Diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate

Diethyl 2-methylmalonate (4.31 mL, 25.0 mmol) was dissolved in 25 mL ofanhydrous DMF. This solution was cooled to 0° C. under an atmosphere ofnitrogen. Sodium hydride (1.04 g, 26 mmol, 60% by weight in mineral oil)was slowly added to the solution. The resulting mixture was allowed tostir for 3 minutes at 0° C., and then at room temperature for 10minutes. 2-Bromo-1-fluoro-4-nitrobenzene (5.00 g, 22.7 mmol) was quicklyadded and the mixture turned bright red. After stirring for 10 minutesat room temperature, the crude mixture was evaporated to dryness andthen partitioned between dichloromethane and a saturated aqueoussolution of sodium chloride. The layers were separated and the organicphase was washed twice with a saturated aqueous solution of sodiumchloride. The organics were concentrated to yield diethyl2-(2-bromo-4-nitrophenyl)-2-methylmalonate (8.4 g, 99%) as a pale yellowoil which was used without further purification. Retention time 1.86min.

Step b: 2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol

Diethyl 2-(2-bromo-4-nitrophenyl)-2-methylmalonate (8.12 g, 21.7 mmol)was dissolved in 80 mL of anhydrous tetrahydrofuran (THF) under anatmosphere of nitrogen. The solution was then cooled to 0° C. before asolution of lithium aluminum hydride (23 mL, 23 mmol, 1.0 M in THF) wasadded slowly. The pale yellow solution immediately turned bright redupon the addition of the lithium aluminum hydride. After 5 min, themixture was quenched by the slow addition of methanol while maintainingthe temperature at 0° C. The reaction mixture was then partitionedbetween dichloromethane and 1 N hydrochloric acid. The layers wereseparated and the aqueous layer was extracted three times withdichloromethane. The combined organics were evaporated to dryness andthen purified by column chromatography (SiO₂, 120 g) utilizing agradient of 0-100% ethyl acetate in hexanes over 45 minutes.2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol was isolated as a redsolid (2.0 g, 31%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.34 (d, J=2.6 Hz, 1H),8.16 (dd, J=2.6, 8.9 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 4.78 (t, J=5.2 Hz,2H), 3.98-3.93 (m, 2H), 3.84-3.79 (m, 2H), 1.42 (s, 3H). Retention time0.89 min.

Step c: 3-Bromo-4-(3-methyloxetan-3-yl)aniline

2-(2-Bromo-4-nitrophenyl)-2-methylpropane-1,3-diol (0.145 g, 0.500 mmol)was dissolved in 2.5 mL of anhydrous benzene.Cyanomethylenetributylphosphorane (CMBP) (0.181 g, 0.750 mmol) was thenadded and the solution was allowed to stir at room temperature for 72hours. The mixture was evaporated to dryness and then re-dissolved in 4mL of EtOH. Tin(II) chloride dihydrate (0.564 g, 2.50 mmol) was thenadded and the resulting solution was heated at 70° C. for 1 hour. Themixture was cooled to room temperature and then quenched with asaturated aqueous solution of sodium bicarbonate. The mixture was thenextracted three times with ethyl acetate. The combined ethyl acetateextracts were evaporated to dryness and purified by preparative LC/MS toyield 3-bromo-4-(3-methyloxetan-3-yl)aniline as a pale yellow oil (0.032g, 32%) ¹H NMR (400 MHz, CD₃CN) δ 7.13 (dd, J=0.7, 1.8 Hz, 1H),6.94-6.88 (m, 2H), 6.75 (br s, 2H), 4.98 (d, J=5.6 Hz, 2H), 4.51 (d,J=6.1 Hz, 2H), 1.74 (s, 3H). ESI-MS m/z calc. 241.0, found; 242.1 (M+1)⁺Retention time 0.53 minutes.

Preparation 43: 3-Bromo-4-ethylaniline

Step a: 2-Bromo-1-ethyl-4-nitrobenzene

To a mixture of 1-ethyl-4-nitro-benzene (30 g, 0.20 mol), silver sulfate(62 g, 0.20 mol), concentrated sulfuric acid (180 mL) and water (20 g)was added bromine (20 mL, 0.40 mol) dropwise at ambient temperature.After addition, the mixture was stirred for 2 hours at ambienttemperature, and then was poured into dilute sodium hydrogen sulfitesolution (1 L, 10%). The mixture was extracted with diethylether. Thecombined organics were dried over Na₂SO₄ and then concentrated undervacuum to provide a mixture of 2-bromo-1-ethyl-4-nitrobenzene and1,3-dibromo-2-ethyl-5-nitro-benzene. The mixture was purified by columnchromatography (petroleum ether/EtOAc 100:1) to yield2-bromo-1-ethyl-4-nitrobenzene (25 g) as a yellow oil with a purity of87%. ¹H NMR (300 MHz, CDCl₃) δ 8.39 (d, J=2.4 Hz, 1H), 8.09 (dd, J=2.4,8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 2.83 (q, J=7.5 Hz, 2H), 1.26 (t,J=7.5 Hz, 3H).

Step b: 3-Bromo-4-ethylaniline

To a solution of 2-bromo-1-ethyl-4-nitro-benzene (25 g, 0.019 mol) inMeOH (100 mL) was added Raney-Ni (2.5 g). The reaction mixture washydrogenated under hydrogen (1 atm) at room temperature. After stirringfor 3 hours, the mixture was filtered and concentrated under reducedpressure. The crude material was purified by preparative HPLC to give3-bromo-4-ethylaniline (8.0 g, 48%). ¹H NMR (400 MHz, CDCl₃) δ 6.92 (d,J=8.4 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.52 (dd, J=2.4, 8.4 Hz, 1H),2.57 (q, J=7.6 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H). MS (ESI) m/e (M+H⁺) 200.

3-Bromo-4-iso-propylaniline and 3-bromo-4-tert-butylaniline weresynthesized following preparation 43 above.

Preparation 44: 5-Bromo-2-fluoro-4-methylaniline

Step a: 1-Bromo-4-fluoro-2-methyl-5-nitrobenzene

To a stirred solution of 1-bromo-4-fluoro-2-methyl-benzene (15.0 g, 79.8mmol) in dichloromethane (300 mL) was added nitronium tetrafluoroborate(11.7 g, 87.8 mmol) in portions at 0° C. The mixture was heated atreflux for 5 h and was then poured into ice water. The organic layer wasseparated and the aqueous phase was extracted with dichloromethane (100mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ andevaporated under reduced pressure to give crude1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g), which was useddirectly in the next step.

Step b: 5-Bromo-2-fluoro-4-methylaniline

To a stirred solution of 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0g) in ethanol (300 mL) was added SnCl₂.2H₂O (51.8 g, 0.230 mol) at roomtemperature. The mixture was heated at reflux for 3 h. The solvent wasevaporated under reduced pressure to give a residue, which was pouredinto ice water. The aqueous phase was basified with sat. NaHCO₃ to pH 7.The solid was filtered off and the filtrate was extracted withdichloromethane (200 mL×3). The combined organics were dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The residue waspurified by column chromatography (petroleum ether/EtOAc=10/1) to afford5-bromo-2-fluoro-4-methylaniline (5.0 g, 30% yield for two steps). ¹HNMR (400 MHz, CDCl₃) δ 6.96 (d, J=8.8 Hz, 1H), 6.86 (d, J=11.6 Hz, 1H),3.64 (br, 2H), 2.26 (s, 3H). MS (ESI) m/z (M+H⁺) 204.0.

Preparation 45:1-(Benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-6-methyl-4′-(2H-tetrazol-5-yl)biphenyl-3-yl)cyclopropanecarboxamide

Step a:1-(Benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-6-methyl-4′-(2H-tetrazol-5-yl)biphenyl-3-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide(0.084 g, 0.20 mmol), 4-bromo-2-chlorobenzonitrile (0.043 g, 0.20 mmol),aqueous potassium carbonate (520 μL, 1M), FibreCat 1007 (7 mg), and DMF(1 mL) were combined. The mixture was heated at 80° C. for 18 hours.After cooling, the mixture was filtered and purified by preparative HPLCto provide1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-4′-cyano-6-methylbiphenyl-3-yl)cyclopropanecarboxamide.

Step b:1-(Benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-6-methyl-4′-(2H-tetrazol-5-yl)biphenyl-3-yl)cyclopropanecarboxamide

To1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-4′-cyano-6-methylbiphenyl-3-yl)-cyclopropanecarboxamidewas added ammonium chloride (0.13 g, 2.4 mmol), sodium azide (0.156 g,2.40 mmol) and 1 mL of DMF. The mixture was heated at 110° C. in amicrowave reactor for 10 minutes. After cooling, the mixture wasfiltered and purified by preparative HPLC to provide1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-6-methyl-4′-(2H-tetrazol-5-yl)biphenyl-3-yl)cyclopropanecarboxamide(8.6 mg, 9%). ESI-MS m/z calc. 473.1, found 474.3 (M+1)⁺; retention time1.86 minutes.

Preparation 46: 3-Bromo-4-(3-methyloxetan-3-yl)aniline

Step a: Diethyl 2-(4-bromophenyl)malonate

To a solution of ethyl 2-(4-bromophenyl)acetate (5.0 g, 21 mmol) in dryTHF (40 mL) at −78° C. was added a 2.0M solution of lithiumdiisopropylamide in THF (11 mL, 22 mmol). After stirring for 30 minutesat −78° C., ethyl cyanoformate (2.0 mL, 21 mmol) was added and themixture was allowed to warm to room temperature. After stirring for 48 hat room temperature, the mixture was quenched with water (10 mL). Thereaction was partitioned between 1 N HCl (50 mL) and dichloromethane (50mL), and the organic layer was separated. The organic layer was washedwith 1 N HCl (50 mL), dried over Na₂SO₄ and evaporated. The crudematerial was purified by silica gel chromatography, eluting with 0-20%ethyl acetate in hexanes to give diethyl 2-(4-bromophenyl)malonate (2.6g, 41%) ¹H NMR (400 MHz, DMSO-d6) δ 7.60-7.58 (m, 2H), 7.36-7.34 (m,2H), 5.03 (s, 1H), 4.21-4.09 (m, 4H), 1.20-1.16 (m, 6H).

Step b: Diethyl 2-(4-bromophenyl)-2-methylmalonate

To a solution of diethyl 2-(4-bromophenyl)malonate (1.5 g, 4.8 mmol) indry THF (5 mL) at 0° C. was added sodium hydride (380 mg, 9.5 mmol).After stirring for 30 minutes at 0° C., iodomethane (600 μL, 9.5 mmol)was added and the reaction was allowed to warm to room temperature.After stirring for 12 h at room temperature, the reaction was quenchedwith water (3 mL). The mixture was partitioned between 1 N HCl (10 mL)and dichloromethane (10 mL), and the organic layer was separated. Theorganic layer was washed with 1 N HCl (10 mL), dried over Na₂SO₄ andevaporated. The crude material was purified by silica gelchromatography, eluting with 0-20% ethyl acetate in hexanes, to givediethyl 2-(4-bromophenyl)-2-methylmalonate (850 mg, 55%) ¹H NMR (400MHz, DMSO-d6) δ 7.59-7.55 (m, 2H), 7.31-7.27 (m, 2H), 4.21-4.14 (m, 4H),1.75 (s, 3H), 1.19-1.16 (m, 6H).

Step c: 2-(4-Bromophenyl)-2-methylpropane-1,3-diol

To a solution of diethyl 2-(4-bromophenyl)-2-methylmalonate (850 mg, 2.6mmol) in dry THF (5 mL) at 0° C. was added a 1.0M solution of lithiumaluminum hydride in THF (2.6 mL, 2.6 mmol). After stirring for 2 h at 0°C., the mixture was quenched by slow addition of water (5 mL). Themixture was made acidic by addition of 1N HCl and was then extractedwith dichloromethane (2×20 mL). The organics were combined, dried overNa₂SO₄ and evaporated to give 2-(4-bromophenyl)-2-methylpropane-1,3-diol(500 mg, 79%) ¹H NMR (400 MHz, DMSO-d6) δ 7.47-7.43 (m, 2H), 7.35-7.32(m, 2H), 4.59-4.55 (m, 2H), 3.56-3.51 (m, 4H), 1.17 (s, 3H).

Step d: 3-(4-Bromophenyl)-3-methyloxetane

2-(4-Bromophenyl)-2-methylpropane-1,3-diol (100 mg, 0.41 mmol),triphenyl phosphine (210 mg, 0.82 mmol), and diisopropylazodicarboxylate (160 μL, 0.82 mmol) were combined in toluene (2 mL) andirradiated in the microwave at 140° C. for 10 minutes. The mixture wasdirectly purified by silica gel chromatography eluting with 0-20% ethylacetate in hexanes to give 3-(4-bromophenyl)-3-methyloxetane (39 mg,42%) ¹H NMR (400 MHz, DMSO-d6) δ 7.38-7.34 (m, 2H), 7.26-7.22 (m, 2H),4.82-4.80 (m, 2H), 4.55-4.54 (m, 2H), 1.62 (s, 3H).

Preparation 47: N-(4-bromophenylsulfonyl)acetamide

3-Bromobenzenesulfonamide (470 mg, 2.0 mmol) was dissolved in pyridine(1 mL). To this solution was added DMAP (7.3 mg, 0.060 mmol) and thenacetic anhydride (570 μL, 6.0 mmol). The reaction was stirred for 3 h atroom temperature during which time the reaction changed from a yellowsolution to a clear solution. The solution was diluted with ethylacetate, and then washed with aqueous NH₄Cl solution (×3) and water. Theorganic layer was dried over MgSO₄ and concentrated. The resulting oilwas triturated with hexanes and the precipitate was collected byfiltration to obtain N-(3-bromophenylsulfonyl)-acetamide as a shinywhite solid (280 mg, 51%). ¹H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H),8.01 (t, J=1.8 Hz, 1H), 7.96-7.90 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 1.95(s, 3H); HPLC ret. time 1.06 min; ESI-MS 278.1 m/z (MH⁺).

Assays

Assays for Detecting and Measuring ΔF508-CFTR Correction Properties ofCompounds

A. Membrane Potential Optical Methods for Assaying ΔF508-CFTR ModulationProperties of Compounds

The optical membrane potential assay utilized voltage-sensitive FRETsensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y.Tsien (1995) “Voltage sensing by fluorescence resonance energy transferin single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

These voltage sensitive assays are based on the change in fluorescenceresonant energy transfer (FRET) between the membrane-soluble,voltage-sensitive dye, DiSBAC₂(3), and a fluorescent phospholipid,CC2-DMPE, which is attached to the outer leaflet of the plasma membraneand acts as a FRET donor. Changes in membrane potential (V_(m)) causethe negatively charged DiSBAC₂(3) to redistribute across the plasmamembrane and the amount of energy transfer from CC2-DMPE changesaccordingly. The changes in fluorescence emission were monitored usingVIPR™ II, which is an integrated liquid handler and fluorescent detectordesigned to conduct cell-based screens in 96- or 384-well microtiterplates.

1. Identification of Correction Compounds

To identify small molecules that correct the trafficking defectassociated with ΔF508-CFTR; a single-addition HTS assay format wasdeveloped. The cells were incubated in serum-free medium for 16 hrs at37° C. in the presence or absence (negative control) of test compound.As a positive control, cells plated in 384-well plates were incubatedfor 16 hrs at 27° C. to “temperature-correct” ΔF508-CFTR. The cells weresubsequently rinsed 3× with Krebs Ringers solution and loaded with thevoltage-sensitive dyes. To activate ΔF508-CFTR, 10 μM forskolin and theCFTR potentiator, genistein (20 μM), were added along with Cl⁻-freemedium to each well. The addition of Cl⁻-free medium promoted Cl⁻ effluxin response to ΔF508-CFTR activation and the resulting membranedepolarization was optically monitored using the FRET-basedvoltage-sensor dyes.

2. Identification of Potentiator Compounds

To identify potentiators of ΔF508-CFTR, a double-addition HTS assayformat was developed. During the first addition, a Cl⁻-free medium withor without test compound was added to each well. After 22 sec, a secondaddition of Cl⁻-free medium containing 2-10 μM forskolin was added toactivate ΔF508-CFTR. The extracellular Cl⁻ concentration following bothadditions was 28 mM, which promoted Cl⁻ efflux in response to ΔF508-CFTRactivation and the resulting membrane depolarization was opticallymonitored using the FRET-based voltage-sensor dyes. 3. Solutions BathSolution #1: (in mM) NaCl 160, KCl 4.5, CaCl₂2, MgCl₂ 1, HEPES 10, pH7.4 with NaOH.

Chloride-free bath solution: Chloride salts in Bath Solution #1 aresubstituted with gluconate salts.

CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at −20°C.

DiSBAC₂(3): Prepared as a 10 mM stock in DMSO and stored at −20° C.

4. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used foroptical measurements of membrane potential. The cells are maintained at37° C. in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1× pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For all opticalassays, the cells were seeded at 30,000/well in 384-well matrigel-coatedplates and cultured for 2 hrs at 37° C. before culturing at 27° C. for24 hrs for the potentiator assay. For the correction assays, the cellsare cultured at 27° C. or 37° C. with and without compounds for 16-24hours

B. Electrophysiological Assays for Assaying ΔF508-CFTR ModulationProperties of Compounds

1. Using Chamber Assay

Using chamber experiments were performed on polarized epithelial cellsexpressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulatorsidentified in the optical assays. FRT^(ΔF508-CFTR) epithelial cellsgrown on Costar Snapwell cell culture inserts were mounted in an Ussingchamber (Physiologic Instruments, Inc., San Diego, Calif.), and themonolayers were continuously short-circuited using a Voltage-clampSystem (Department of Bioengineering, University of Iowa, IA, and,Physiologic Instruments, Inc., San Diego, Calif.). Transepithelialresistance was measured by applying a 2-mV pulse. Under theseconditions, the FRT epithelia demonstrated resistances of 4 KΩ/cm² ormore. The solutions were maintained at 27° C. and bubbled with air. Theelectrode offset potential and fluid resistance were corrected using acell-free insert. Under these conditions, the current reflects the flowof Cl⁻ through ΔF508-CFTR expressed in the apical membrane. The I_(SC)was digitally acquired using an MP100A-CE interface and AcqKnowledgesoftware (ν3.2.6; BIOPAC Systems, Santa Barbara, Calif.).

2. Identification of Correction Compounds

Typical protocol utilized a basolateral to apical membrane Cl⁻concentration gradient. To set up this gradient, normal ringer was usedon the basolateral membrane, whereas apical NaCl was replaced byequimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give alarge Cl⁻ concentration gradient across the epithelium. All experimentswere performed with intact monolayers. To fully activate ΔF508-CFTR,forskolin (10 μM) and the PDE inhibitor, IBMX (100 μM), were appliedfollowed by the addition of the CFTR potentiator, genistein (50 μM).

As observed in other cell types, incubation at low temperatures of FRTcells stably expressing ΔF508-CFTR increases the functional density ofCFTR in the plasma membrane. To determine the activity of correctioncompounds, the cells were incubated with 10 μM of the test compound for24 hours at 37° C. and were subsequently washed 3× prior to recording.The cAMP- and genistein-mediated I_(SC) in compound-treated cells wasnormalized to the 27° C. and 37° C. controls and expressed as percentageactivity. Preincubation of the cells with the correction compoundsignificantly increased the cAMP- and genistein-mediated I_(SC) comparedto the 37° C. controls.

3. Identification of Potentiator Compounds

Typical protocol utilized a basolateral to apical membrane Cl⁻concentration gradient. To set up this gradient, normal ringers was usedon the basolateral membrane and was permeabilized with nystatin (360μg/ml), whereas apical NaCl was replaced by equimolar sodium gluconate(titrated to pH 7.4 with NaOH) to give a large Cl⁻ concentrationgradient across the epithelium. All experiments were performed 30 minafter nystatin permeabilization. Forskolin (10 μM) and all testcompounds were added to both sides of the cell culture inserts. Theefficacy of the putative ΔF508-CFTR potentiators was compared to that ofthe known potentiator, genistein.

4. Solutions

Basolateral solution (in mM): NaCl (135), CaCl₂ (1.2), MgCl₂ (1.2),K₂HPO₄ (2.4), KHPO₄ (0.6),N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) (10), anddextrose (10). The solution was titrated to pH 7.4 with NaOH.

Apical solution (in mM): Same as basolateral solution with NaCl replacedwith Na Gluconate (135).

5. Cell Culture

Fisher rat epithelial (FRT) cells expressing ΔF508-CFTR(FRT^(ΔF508-CFTR)) were used for Ussing chamber experiments for theputative ΔF508-CFTR modulators identified from our optical assays. Thecells were cultured on Costar Snapwell cell culture inserts and culturedfor five days at 37° C. and 5% CO₂ in Coon's modified Ham's F-12 mediumsupplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100μg/ml streptomycin. Prior to use for characterizing the potentiatoractivity of compounds, the cells were incubated at 27° C. for 16-48 hrsto correct for the ΔF508-CFTR. To determine the activity of correctionscompounds, the cells were incubated at 27° C. or 37° C. with and withoutthe compounds for 24 hours.

6. Whole-Cell Recordings

The macroscopic ΔF508-CFTR current (IΔF508) in temperature- and testcompound-corrected NIH3T3 cells stably expressing ΔF508-CFTR weremonitored using the perforated-patch, whole-cell recording. Briefly,voltage-clamp recordings of I_(ΔF508) were performed at room temperatureusing an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.,Foster City, Calif.). All recordings were acquired at a samplingfrequency of 10 kHz and low-pass filtered at 1 kHz. Pipettes had aresistance of 5-6 MΩ when filled with the intracellular solution. Underthese recording conditions, the calculated reversal potential for Cl⁻(E_(Cl)) at room temperature was −28 mV. All recordings had a sealresistance >20 GΩ and a series resistance <15 MΩ. Pulse generation, dataacquisition, and analysis were performed using a PC equipped with aDigidata 1320 A/D interface in conjunction with Clampex 8 (AxonInstruments Inc.). The bath contained <250 μl of saline and wascontinuously perfused at a rate of 2 ml/min using a gravity-drivenperfusion system.

7. Identification of Correction Compounds

To determine the activity of correction compounds for increasing thedensity of functional ΔF508-CFTR in the plasma membrane, we used theabove-described perforated-patch-recording techniques to measure thecurrent density following 24-hr treatment with the correction compounds.To fully activate ΔF508-CFTR, 10 μM forskolin and 20 μM genistein wereadded to the cells. Under our recording conditions, the current densityfollowing 24-hr incubation at 27° C. was higher than that observedfollowing 24-hr incubation at 37° C. These results are consistent withthe known effects of low-temperature incubation on the density ofΔF508-CFTR in the plasma membrane. To determine the effects ofcorrection compounds on CFTR current density, the cells were incubatedwith 10 μM of the test compound for 24 hours at 37° C. and the currentdensity was compared to the 27° C. and 37° C. controls (% activity).Prior to recording, the cells were washed 3× with extracellularrecording medium to remove any remaining test compound. Preincubationwith 10 μM of correction compounds significantly increased the cAMP- andgenistein-dependent current compared to the 37° C. controls.

8. Identification of Potentiator Compounds

The ability of ΔF508-CFTR potentiators to increase the macroscopicΔF508-CFTR Cl⁻ current (I_(ΔF508)) in NIH3T3 cells stably expressingΔF508-CFTR was also investigated using perforated-patch-recordingtechniques. The potentiators identified from the optical assays evoked adose-dependent increase in I_(ΔF508) with similar potency and efficacyobserved in the optical assays. In all cells examined, the reversalpotential before and during potentiator application was around −30 mV,which is the calculated E_(Cl) (−28 mV).

9. Solutions

Intracellular solution (in mM): Cs-aspartate (90), CsCl (50), MgCl₂ (1),HEPES (10), and 240 μg/ml amphotericin-B (pH adjusted to 7.35 withCsOH).

Extracellular solution (in mM): N-methyl-D-glucamine (NMDG)-Cl (150),MgCl₂ (2), CaCl₂ (2), HEPES (10) (pH adjusted to 7.35 with HCl).

10. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used forwhole-cell recordings. The cells are maintained at 37° C. in 5% CO₂ and90% humidity in Dulbecco's modified Eagle's medium supplemented with 2mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME, 1× pen/strep, and 25mM HEPES in 175 cm² culture flasks. For whole-cell recordings,2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslipsand cultured for 24-48 hrs at 27° C. before use to test the activity ofpotentiators; and incubated with or without the correction compound at37° C. for measuring the activity of correctors.

11. Single-Channel Recordings

The single-channel activities of temperature-corrected ΔF508-CFTR stablyexpressed in NIH3T3 cells and activities of potentiator compounds wereobserved using excised inside-out membrane patch. Briefly, voltage-clamprecordings of single-channel activity were performed at room temperaturewith an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). Allrecordings were acquired at a sampling frequency of 10 kHz and low-passfiltered at 400 Hz. Patch pipettes were fabricated from Corning KovarSealing #7052 glass (World Precision Instruments, Inc., Sarasota, Fla.)and had a resistance of 5-8 MΩ when filled with the extracellularsolution. The ΔF508-CFTR was activated after excision, by adding 1 mMMg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalyticsubunit (PKA; Promega Corp. Madison, Wis.). After channel activitystabilized, the patch was perfused using a gravity-driven microperfusionsystem. The inflow was placed adjacent to the patch, resulting incomplete solution exchange within 1-2 sec. To maintain ΔF508-CFTRactivity during the rapid perfusion, the nonspecific phosphataseinhibitor F— (10 mM NaF) was added to the bath solution. Under theserecording conditions, channel activity remained constant throughout theduration of the patch recording (up to 60 min). Currents produced bypositive charge moving from the intra- to extracellular solutions(anions moving in the opposite direction) are shown as positivecurrents. The pipette potential (V_(p)) was maintained at 80 mV.

Channel activity was analyzed from membrane patches containing ≦2 activechannels. The maximum number of simultaneous openings determined thenumber of active channels during the course of an experiment. Todetermine the single-channel current amplitude, the data recorded from120 sec of ΔF508-CFTR activity was filtered “off-line” at 100 Hz andthen used to construct all-point amplitude histograms that were fittedwith multigaussian functions using Bio-Patch Analysis software(Bio-Logic Comp. France). The total microscopic current and openprobability (PO) were determined from 120 sec of channel activity. TheP_(o) was determined using the Bio-Patch software or from therelationship P_(o)=I/i(N), where I=mean current, i=single-channelcurrent amplitude, and N=number of active channels in patch.

12. Solutions

-   Extracellular solution (in mM): NMDG (150), aspartic acid (150),    CaCl₂ (5), MgCl₂ (2), and HEPES (10) (pH adjusted to 7.35 with Tris    base).-   Intracellular solution (in mM): NMDG-Cl (150), MgCl₂ (2), EGTA (5),    TES (10), and Tris base (14) (pH adjusted to 7.35 with HCl).

13. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used forexcised-membrane patch-clamp recordings. The cells are maintained at 37°C. in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1× pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For singlechannel recordings, 2,500-5,000 cells were seeded onpoly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27°C. before use.

The exemplified compounds of Table 1 have an activity of less than 20 mMas measured using the assays described hereinabove.

VIII. OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Each R₁ isindependently an optionally substituted C₁₋₆ aliphatic, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted C₃₋₁₀ membered cycloaliphatic or an optionally substituted 4to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, orhydroxy, provided that at least one R₁ is an optionally substituted arylor an optionally substituted heteroaryl and said R₁ is attached to the3- or 4-position of the phenyl ring; R₂ is hydrogen, an optionallysubstituted C₁₋₆ aliphatic, an optionally substituted C₃₋₆cycloaliphatic, an optionally substituted phenyl, or an optionallysubstituted heteroaryl; Ring A is an optionally substitutedcycloaliphatic or an optionally substituted heterocycloaliphatic wherethe atoms of ring A adjacent to C* are carbon atoms; Each R₄ is anoptionally substituted aryl or an optionally substituted heteroaryl; andn is 1, 2, 3, 4, or
 5. 2. The compound of claim 1, wherein the one R₁attached to the 3- or 4-position of the phenyl ring is an aryl orheteroaryl optionally substituted with 1, 2, or 3 of R^(A), whereinR^(A) is -Z^(A)R₅; in which each Z^(A) is independently a bond or anoptionally substituted branched or straight C₁₋₆ aliphatic chain whereinup to two carbon units of Z^(A) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—,—NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—,—NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or—NR^(B)SO₂NR^(B)—; each R₅ is independently R^(B), halo, —B(OH)₂, —OH,—NH₂, —NO₂, —CN, or —OCF₃; and each R^(B) is independently hydrogen, anoptionally substituted C₁₋₈ aliphatic group, an optionally substitutedcycloaliphatic, an optionally substituted heterocycloaliphatic, anoptionally substituted aryl, or an optionally substituted heteroaryl. 3.The compound of claim 2, wherein the one R₁ attached to the 3- or4-position of the phenyl ring is a phenyl optionally substituted with 1,2, or 3 of R^(A).
 4. The compound of claim 3, wherein the one R₁attached to the 3- or 4-position of the phenyl ring is a phenylsubstituted with one of R^(A), wherein R^(A) is -Z^(A)R₅; each Z^(A) isindependently a bond or an optionally substituted branched or straightC₁₋₆ aliphatic chain wherein up to two carbon units of Z^(A) areoptionally and independently replaced by —O—, —NHC(O)—, —C(O)NR^(B)—,—SO₂—, —NHSO₂—, —NHC(O)—, —SO—, —NR^(B)SO₂—, —SO₂NH—, —SO₂NR^(B)—, —NH—,or —C(O)O—.
 5. The compound of claim 4, wherein one carbon unit of Z^(A)is replaced by —O—, —NHC(O)—, —C(O)NR^(B)—, —SO₂—, —NHSO₂—, —NHC(O)—,—SO—, —NR^(B)SO₂—, —SO₂NH—, —SO₂NR^(B)—, —NH—, or —C(O)O—.
 6. Thecompound of claim 2, wherein R₅ is independently an optionallysubstituted aliphatic, an optionally substituted cycloaliphatic, anoptionally substituted heterocycloaliphatic, an optionally substitutedaryl, an optionally substituted heteroaryl, or halo.
 7. The compound ofclaim 1, wherein the one R₁ attached to the 3- or 4-position of thephenyl ring is heteroaryl optionally substituted with 1, 2, or 3 ofR^(A).
 8. The compound of claim 7, wherein the one R₁ attached to the 3-or 4-position of the phenyl ring is a 5 or 6 membered heteroaryl having1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, wherein the heteroaryl is substituted with one of R^(A), whereinR^(A) is -Z^(A)R₅; each Z^(A) is independently a bond or an optionallysubstituted branched or straight C₁₋₆ aliphatic chain wherein up to twocarbon units of Z^(A) are optionally and independently replaced by —O—,—NHC(O)—, —C(O)NR^(B)—, —SO₂—, —NHSO₂—, —NHC(O)—, —SO—, —NR^(B)SO₂—,—SO₂NH—, —SO₂NR^(B)—, —NH—, or —C(O)O—.
 9. The compound of claim 8,wherein one carbon unit of Z^(A) is replaced by —O—, —NHC(O)—,—C(O)NR^(B)—, —SO₂—, —NHSO₂—, —NHC(O)—, —SO—, —NR^(B)SO₂—, —SO₂NH—,—SO₂NR^(B)—, —NH—, or —C(O)O—.
 10. The compound of claim 7, wherein R₅is independently an optionally substituted aliphatic, an optionallysubstituted cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, an optionallysubstituted heteroaryl, or halo.
 11. The compound of claim 2, wherein R₁is:

Wherein W₁ is —C(O)—, —SO₂—, —NHC(O)—, or —CH₂—; and D is H, hydroxy, oran optionally substituted aliphatic, an optionally substitutedcycloaliphatic, an optionally substituted alkoxy, and amino.
 12. Thecompound of claim 10, wherein D is OH, an optionally substituted C₁₋₆aliphatic, an optionally substituted C₃-C₈ cycloaliphatic, an optionallysubstituted alkoxy, or an optionally substituted amino.
 13. The compoundof claim 12, wherein D is an optionally substituted amino of the formula

wherein each of A and B is independently H, an optionally substitutedC₁₋₆ aliphatic, an optionally substituted C₃-C₈ cycloaliphatic, anoptionally substituted 3-8 membered heterocycloaliphatic, acyl,sulfonyl, or A and B, taken together, form an optionally substituted 3-7membered heterocycloaliphatic ring.
 14. The compound of claim 10,wherein R₁ is:

wherein: W₁ is —C(O)—, —SO₂—, —NHC(O)—, or —CH₂—; Each of A and B isindependently H or an optionally substituted C₁₋₆ aliphatic; or A and B,taken together, form an optionally substituted 4-7 memberedheterocycloaliphatic ring.
 15. The compound of claim 13, wherein A is Hand B is C₁₋₆ aliphatic optionally substituted with 1, 2, or 3 of halo,oxo, CN, hydroxy, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted hydroxyalkyl, anoptionally substituted alkoxy, an optionally substituted alkoxyalkyl, anoptionally substituted cycloaliphatic, amino, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, or an optionallysubstituted heteroaryl.
 16. The compound of claim 13, wherein A and B,taken together with the nitrogen atom, form an optionally substituted3-7 membered heterocycloaliphatic ring.
 17. The compound of claim 15,wherein A and B, taken together with the nitrogen atom, form anoptionally substituted pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolidin-3-yl, and 1,4-diazepan-1-yl.
 18. The compound ofclaim 15, wherein the heterocycloaliphatic ring is optionallysubstituted with 1, 2, or 3 of halo, oxo, alkyl, aryl, heteroaryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, amido, or carboxy.19. The compound of claim 1, wherein R₂ is hydrogen or methyl.
 20. Thecompound of claim 1, wherein ring A is an unsubstituted C₃₋₇cycloaliphatic or a 3-8 membered heterocycloaliphatic.
 21. The compoundof claim 20, wherein ring A is an unsubstituted cyclopropyl, anunsubstituted cyclopentyl, an unsubstituted cyclohexyl, or anunsubstituted tetrahydropyranyl.
 22. The compound of claim 21, whereinring A is an unsubstituted cyclopropyl.
 23. The compound of claim 1,wherein R₄ is an aryl or heteroaryl optionally substituted with 1, 2, or3 of -Z^(C)R₈, wherein each Z^(C) is independently a bond or anoptionally substituted branched or straight C₁₋₆ aliphatic chain whereinup to two carbon units of Z^(C) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(C)—, —CONR^(C)NR^(C)—, —CO₂—, —OCO—,—NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—, —NR^(C)NR^(C)—,—NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—, —NR^(C)SO₂—, or—NR^(C)SO₂NR^(C)—; each R₈ is independently R^(C), halo, —OH, —NH₂,—NO₂, —CN, or —OCF₃; and each R^(C) is independently hydrogen, anoptionally substituted C₁₋₈ aliphatic group, an optionally substitutedcycloaliphatic, an optionally substituted heterocycloaliphatic, anoptionally substituted aryl, or an optionally substituted heteroaryl.24. The compound of claim 23, wherein R₄ is an aryl optionallysubstituted with 1, 2, or 3 of -Z^(C)R₈.
 25. The compound of claim 24,wherein R₄ is phenyl optionally substituted with 1, 2, or 3 of -Z^(C)R₈.26. The compound of claim 23, wherein R₄ is a heteroaryl optionallysubstituted with 1, 2, or 3 of -Z^(C)R₈.
 27. The compound of claim 23,wherein R₄ is one selected from


28. A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein Each R₁ isindependently an optionally substituted C₁₋₆ aliphatic, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted 3 to 10 membered cycloaliphatic, or an optionallysubstituted 4 to 10 membered heterocycloaliphatic, each of which isoptionally substituted with 1, 2, or 3 of R^(A); Each R^(A) is -Z^(A)R₅,wherein each Z^(A) is independently a bond or an optionally substitutedbranched or straight C₁₋₆ aliphatic chain wherein up to two carbon unitsof Z^(A) are optionally and independently replaced by —CO—, —CS—,—CONR^(B)—, —CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—,—NR^(B)CONR^(B)—, —OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—,—SO₂—, —NR^(B)—, —SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—; Each R₅is independently R^(B), halo, —OH, —NH₂, —NO₂, —CN, or —OCF₃; Each R^(B)is independently hydrogen, an optionally substituted C₁₋₈ aliphaticgroup, an optionally substituted cycloaliphatic, an optionallysubstituted heterocycloaliphatic, an optionally substituted aryl, or anoptionally substituted heteroaryl; R₂ is C₁₋₄ aliphatic, C₃₋₆cycloaliphatic, phenyl, or heteroaryl, each of which is optionallysubstituted, or R₂ is hydrogen; Ring A is an optionally substituted C₃₋₇cycloaliphatic or an optionally substituted C₃₋₇ heterocycloaliphaticwhere the atoms of ring A adjacent to C* are carbon atoms, and said ringA is optionally substituted with 1, 2, or 3 of -Z^(B)R₇, wherein eachZ^(B) is independently a bond, or an optionally substituted branched orstraight C₁₋₄ aliphatic chain wherein up to two carbon units of Z^(B)are optionally and independently replaced by —CO—, —CS—, —CONR^(B)—,—CONR^(B)NR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—,—OCONR^(B)—, —NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—,—SO₂NR^(B)—, —NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—; Each R₇ is independentlyR^(B), halo, —OH, —NH₂, —NO₂, —CN, or —OCF₃; Each R₄ is independently anaryl or heteroaryl, each of which is optionally substituted with 1, 2,or 3 of -Z^(C)R₈, wherein each Z^(C) is independently a bond or anoptionally substituted branched or straight C₁₋₆ aliphatic chain whereinup to two carbon units of Z^(C) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(C)—, —CONR^(C)NR^(C)—, —CO₂—, —OCO—,—NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—, —NR^(C)NR^(C)—,—NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—, —NR^(C)SO₂—, or—NR^(C)SO₂NR^(C)—. Each R₈ is independently R^(C), halo, —OH, —NH₂,—NO₂, —CN, or —OCF₃. Each R^(C) is independently an optionallysubstituted C₁₋₈ aliphatic group, an optionally substitutedcycloaliphatic, an optionally substituted heterocycloaliphatic, anoptionally substituted aryl, or an optionally substituted heteroaryl;and Each n is 1-4.
 29. The compound of claim 28, wherein Z^(A) isindependently a bond or an optionally substituted branched or straightC₁₋₆ aliphatic chain wherein one carbon unit of Z^(A) is optionallyreplaced by —SO₂—, —CONR^(B)—, or —SO₂NR^(B)—.
 30. The compound of claim29, wherein Z^(A) is an optionally substituted branched or straight C₁₋₆aliphatic chain wherein one carbon unit of Z^(A) is optionally replacedby —SO₂—.
 31. The compound of claim 30, wherein R₅ is an optionallysubstituted heteroaryl or an optionally substitutedheterocycloaliphatic.
 32. The compound of claim 31, wherein R₅ is anoptionally substituted heterocycloaliphatic and R₅ attaches directly tothe —SO₂— via one ring nitrogen.
 33. The compound of claim 28, whereinring A is an unsubstituted cyclopropyl.
 34. The compound of claim 33,wherein the compound has formula IIc:

or a pharmaceutically acceptable salt thereof, wherein: T is anoptionally substituted C₁₋₂ aliphatic chain, wherein each of the carbonunits is optionally and independently replaced by —CO—, —CS—, —COCO—,—SO₂—, —B(OH)—, or —B(O(C₁₋₆ alkyl))-; Each of R₁ is independently anoptionally substituted C₁₋₆ aliphatic, an optionally substituted aryl,an optionally substituted heteroaryl, an optionally substituted 3 to 10membered cycloaliphatic, an optionally substituted 4 to 10 memberedheterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy; EachR^(A) is independently -Z^(A)R₅, wherein each Z^(A) is independently abond or an optionally substituted branched or straight C₁₋₆ aliphaticchain wherein up to two carbon units of Z^(A) are optionally andindependently replaced by —CO—, —CS—, —CONR^(B)—, —CONR^(B)NR^(B)—,—CO₂—, —OCO—, —NR^(B)CO₂—, —O—, —NR^(B)CONR^(B)—, —OCONR^(B)—,—NR^(B)NR^(B)—, —NR^(B)CO—, —S—, —SO—, —SO₂—, —NR^(B)—, —SO₂NR^(B)—,—NR^(B)SO₂—, or —NR^(B)SO₂NR^(B)—; Each R₅ is independently R^(B), halo,—OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; or two R^(A), taken together withatoms to which they are attached, form a 3-8 membered saturated,partially unsaturated, or aromatic ring with up to 3 ring membersindependently selected from the group consisting of O, NH, NR^(B), andS, provided that one R^(A) is attached to carbon 3″ or 4″; Each R^(B) isindependently hydrogen, an optionally substituted C₁₋₈ aliphatic group,an optionally substituted cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, or an optionallysubstituted heteroaryl; and n is 2 or 3 provided that when n is 3, afirst R₁ is attached ortho relative to the phenyl ring substituted withR^(A) and that a second one R₁ is attached para relative to the phenylring substituted with R^(A).
 35. The compound according to claim 34,wherein T is —CH₂—, —CF₂—, —C(CH₃)₂—,


36. The compound according to claim 35, wherein one R₁ is -Z^(E)R₉,wherein each Z^(E) is independently a bond or an optionally substitutedbranched or straight C₁₋₆ aliphatic chain wherein up to two carbon unitsof Z^(E) are optionally and independently replaced by —CO—, —CONR^(E)—,—CO₂—, —O—, —S—, —SO—, —SO₂—, —NR^(E)—, or —SO₂NR^(E)—; Each R⁹ isindependently hydrogen, R^(E), halo, —OH, —NH₂, —CN, —CF₃, or —OCF₃; andEach R^(E) is independently an optionally substituted C₁₋₈ aliphatic, anoptionally substituted cycloaliphatic, an optionally substitutedheterocycloaliphatic, an optionally substituted aryl, or an optionallysubstituted heteroaryl.
 37. The compound of claim 35, wherein the one R₁is attached ortho relative to the phenyl ring substituted with R^(A).38. The compound of claim 37, wherein the other R₁ is selected from thegroup consisting of H, methyl, ethyl, iso-propyl, tert-butyl, F, Cl,CF₃, —OCH₃, —OCH₂CH₃, —O-(iso-propyl), —O-(tert-butyl), and —OCF₃ and isattached para relative to the phenyl ring substituted with R^(A). 39.The compound of claim 34, wherein one R^(A) is -Z^(A)R₅; wherein Z^(A)is selected from CONH, CON(C₁₋₆ alkyl), NHCO, SO₂NH, SO₂N(C₁₋₆ alkyl),NHSO₂, CH₂NHSO₂, CH₂N(CH₃)SO₂, CH₂NHCO, CH₂N(CH₃)CO, COO, SO₂, SO, orCO.
 40. The compound of claim 39, wherein Z^(A) is CONH and R₅ is H, anoptionally substituted straight or branched C₁₋₆ aliphatic, anoptionally substituted C₃₋₁₀ cycloaliphatic, or an optionallysubstituted 3-8 membered heterocycloalkyl.
 41. The compound of claim 40,wherein R₅ is methyl, ethyl, n-propyl, iso-propyl, 3-methylbutyl,3,3-dimethylbutyl, 2-methylpropyl, tert-butyl, 2-(dimethylamino)ethyl,cyclopropylmethyl, cyclohexylmethyl, 2-(cyclohexen-1-yl)ethyl,3-(morpholin-4-yl)propyl, 2-(morpholin-4-yl)ethyl,2-(1H-imidazol-4-yl)ethyl, tetrahydrofuran-2-yl-methyl,2-(pyrid-2-yl)ethyl, (1-ethyl-pyrrolidin-2-yl)methyl,1-hydroxymethylpropyl, 1-hydroxymethylbutyl, 1-hydroxymethylpentyl,1-hydroxymethyl-2-hydroxyethyl, 1-hydroxymethyl-2-methylpropyl,1-hydroxymethyl-3-methyl-butyl, 2,2-dimethyl-1-hydroxymethyl-propyl,1,1-di(hydroxymethyl)ethyl, 1,1-di(hydroxymethyl)propyl, 3-ethoxypropyl,2-acetoaminoethyl, 2-(2′-hydroxyethoxy)ethyl, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,2-hydroxy-1-methylethyl, 2-methoxyethyl, 3-methoxypropyl, 2-cyanoethyl,aminoformylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or3-oxo-isoxazolidin-4-yl.
 42. The compound of claim 41, wherein Z^(A) is—CON(C₁₋₆ alkyl)- and R₅ is an optionally substituted C₁₋₆ aliphatic oran optionally substituted C₃₋₈ cycloaliphatic.
 43. The compound of claim39, wherein Z^(A) is —CH₂NHCO— and R₅ is an optionally substitutedstraight or branched C₁₋₆ aliphatic, an optionally substituted C₃₋₈cycloaliphatic, an optionally substituted alkoxy, or an optionallysubstituted heteroaryl.
 44. The compound of claim 43, wherein R₅ ismethyl, ethyl, 1-ethylpropyl, 2-methylpropyl, 1-methylpropyl,2,2-dimethylpropyl, n-propyl, iso-propyl, n-butyl, tert-butyl,cyclopentyl, dimethylaminomethyl, methoxymethyl,(2′-methoxyethoxy)methyl, (2′-methoxy)ethoxy, methoxy, ethoxy,iso-propoxy, tert-butoxy, or pyrazinyl.
 45. The compound of claim 39,wherein Z^(A) is —CH₂N(CH₃)CO— and R₅ is an optionally substitutedstraight or branched C₁₋₆ aliphatic, an optionally substituted C₃₋₈cycloaliphatic, or an optionally substituted heteroaryl.
 46. Thecompound of claim 45, wherein R₅ is methyl, ethyl, iso-propyl, n-propyl,n-butyl, tert-butyl, 1-ethylpropyl, 2-methylpropyl, 2,2-dimethylpropyl,or cyclopentyl.
 47. The compound of claim 39, wherein Z^(A) is SO₂NH andR₅ is H, an optionally substituted straight or branched C₁₋₆ aliphatic,an optionally substituted C₃₋₈ cycloaliphatic, or an optionallysubstituted 3-8 membered heterocycloaliphatic.
 48. The compound of claim47, wherein R₅ is a straight or branched C₁₋₆ aliphatic, C₃₋₈cycloaliphatic, or 3-8 membered heterocycloaliphatic, each of which isoptionally substituted with 1-3 of halo, oxo, hydroxy, an optionallysubstituted C₁₋₆ aliphatic, an optionally substituted C₃₋₈cycloaliphatic, an optionally substituted 3-8 memberedheterocycloaliphatic, an optionally substituted C₆₋₁₀ aryl, anoptionally substituted 5-10 membered heteroaryl, an optionallysubstituted alkoxy, amino, amido, carboxyl, or acyl.
 49. The compound ofclaim 48, wherein R₅ is H, methyl, ethyl, n-propyl, iso-propyl,tert-butyl, 3,3-dimethylbutyl, CH₂CH₂OH, CH₂CH₂OCH₃, CH(CH₃)CH₂OH,CH₂CH(CH₃)OH, CH(CH₂OH)₂, CH₂CH(OH)CH₂OH, CH₂CH(OH)CH₂CH₃, C(CH₃)₂CH₂OH,CH(CH₂CH₃)CH₂OH, CH₂CH₂OCH₂CH₂OH, C(CH₃)(CH₂OH)₂, CH(CH₃)C(O)OH,CH(CH₂OH)C(O)OH, CH₂C(O)OH, CH₂CH₂C(O)OH, CH₂CH(OH)CH₂C(O)OH,CH₂CH₂N(CH₃)₂, CH₂CH₂NHC(O)CH₃, CH(CH(CH₃)₂)CH₂OH, CH(CH₂CH₂CH₃)CH₂OH,tetrahydrofuran-2-ylmethyl, furylmethyl, (5-methylfuryl)-methyl,2-pyrrolidinylethyl, 2-(1-methylpyrrolidinyl)-ethyl,2-(morpholin-4-yl)-ethyl, 3-(morpholin-4-yl)-propyl, C(CH₂CH₃)(CH₂OH)₂,2-(1H-imidazol-4-yl)ethyl, 3-(1H-imidazol-1-yl)-propyl,2-(pyridin-2-yl)-ethyl, cyclobutyl, cyclopentyl, cyclohexyl, or3-oxo-isoxazolidin-4-yl.
 50. The compound of claim 39, wherein Z^(A) isSO₂N(C₁₋₆ alkyl) and R₅ is an optionally substituted straight orbranched C₁₋₆ aliphatic or an optionally substituted cycloaliphatic. 51.The compound of claim 39, wherein Z^(A) is CH₂NHSO₂ and R₅ is anoptionally substituted C₁₋₆ aliphatic.
 52. The compound of claim 39,wherein Z^(A) is CH₂N(C₁₋₆ aliphatic)SO₂ and R₅ is an optionallysubstituted C₁₋₆ aliphatic.
 53. The compound of claim 39, wherein Z^(A)is SO and R₅ is an optionally substituted straight or branched C₁₋₆aliphatic.
 54. The compound of claim 39, wherein Z^(A) is SO₂ and R₅ isan optionally substituted straight or branched C₁₋₆ aliphatic or anoptionally substituted 3-8 membered heterocyclic.
 55. The compound ofclaim 54, wherein R₅ is straight or branched C₁₋₆ alkyl or 3-8 memberedheterocycloaliphatic; each of which is optionally substituted with 1, 2,or 3 of oxo, halo, hydroxy, an optionally substituted C₁₋₆ aliphatic, anoptionally substituted aryl, an optionally substituted heteroaryl,carbonyl, amino, or carboxy.
 56. The compound of claim 54, wherein Z^(A)is SO₂ and R₅ is methyl, ethyl, iso-propyl,


57. The compound of claim 39, wherein Z^(A) is CO and R₅ is an amino, anoptionally substituted C₁₋₆ straight or branched aliphatic, or anoptionally substituted 3-8 membered heterocyclic.
 58. The compound ofclaim 57, wherein Z^(A) is CO and R₅ is di-(2-methoxyethyl)amino,di-(2-hydroxyethyl)amino,


59. The compound of claim 39, wherein Z^(A) is —NHCO— and R₅ is C₁₋₆aliphatic, C₁₋₆ alkoxy, amino, or heterocycloaliphatic; each of which isoptionally substituted with 1, 2, or 3 groups independently selectedfrom oxo, halo, hydroxy, an optionally substituted C₁₋₆ aliphatic, anoptionally substituted 3-8 membered heterocycloaliphatic, an optionallysubstituted alkoxy, carbonyl, amino, and carboxy.
 60. The compound ofclaim 59, wherein R₅ is methyl, methoxymethyl, hydroxymethyl,(morpholin-4-yl)-methyl, CH₂COOH, ethoxy, dimethylamino, ormorpholin-4-yl.
 61. The compound of claim 39, wherein the one R^(A) isattached to the carbon 3″ or 4″.
 62. The compound of claim 61, wherein asecond R^(A) is selected from the group consisting of H, R^(B), halo,—OH, —(CH₂)_(r)NR^(B)R^(B), —(CH₂)_(r)OR^(B), —SO₂—R^(B),—NR^(B)—SO₂—R^(B), —SO₂NR^(B)R^(B), —C(O)R^(B), —C(O)OR^(B),—OC(O)OR^(B), —NR^(B)C(O)OR^(B), and —C(O)NR^(B)R^(B); wherein r is 0,1, or 2; and each R^(B) is independently hydrogen, an optionallysubstituted C₁₋₈ aliphatic group, an optionally substitutedcycloaliphatic, an optionally substituted heterocycloaliphatic, anoptionally substituted aryl, or an optionally substituted heteroaryl.63. The compound of claim 62, wherein the second R^(A) is selected fromthe group consisting of H, methyl, ethyl, n-propyl, iso-propyl,tert-butyl, tetrazol-5-yl, F, Cl, CN, —NH₂, —CH₂NH₂, —CH₂CN, —CH₂COOH,—CH₂CH₂COOH, 1,3-dioxo-isoindolin-2-ylmethyl, —OH, —OCH₃, —OCF₃, ethoxy,iso-propoxy, n-propoxy, —CH₂OH, —CH₂CH₂OH, —SO₂CH₃, —NH—SO₂CH₃,—C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)OH, —NHC(O)CH₃, —C(O)NH₂, and—C(O)N(CH₃)₂.
 64. The compound of claim 34, wherein n is 2; R₁ isattached ortho relative to the phenyl ring substituted with R^(A); oneR^(A) is attached to the carbon 4″.
 65. The compound of claim 64,wherein R₁ is selected from the group consisting of H, halo, CF₃, or anoptionally substituted group selected from C₁₋₆ aliphatic, —O(C₁₋₆aliphatic), C₃₋₅ cycloalkyl, 3-6 membered heterocycloalkyl containingone oxygen atom, carboxy, and aminocarbonyl; wherein said C₁₋₆aliphatic, —O(C₁₋₆ aliphatic), C₃₋₅ cycloalkyl, 3-6 memberedheterocycloalkyl containing one oxygen atom, carboxy, or aminocarbonylis optionally substituted with halo, CN, hydroxy, or a group selectedfrom amino, C₁₋₆ aliphatic, alkoxy, amido, C₃₋₈ cycloaliphatic, 3-10membered heterocyclicaliphatic, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl, each of which is further optionally substituted with 1-3 ofhalo or hydroxy.
 66. The compound of claim 65, wherein the R^(A) notattached to the carbon 4″ is H, hydroxy, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₃₋₆ cycloalkyl, or NH₂.
 67. A compound having a structure shown as oneof compound numbers 1-1205 in Table
 1. 68. A pharmaceutical compositioncomprising: (i) a compound according to claim 1; and (ii) apharmaceutically acceptable carrier.
 69. The composition of claim 68,optionally further comprising a mucolytic agent, a bronchodialator, ananti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTRmodulator, or a nutritional agent.
 70. A method of modulating ABCtransporter activity comprising the step of contacting said ABCtransporter with a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Each R₁ isindependently an optionally substituted C₁₋₆ aliphatic, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted C₃₋₁₀ membered cycloaliphatic, an optionally substituted 4to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, orhydroxy, provided that at least one R₁ is an optionally substituted arylor an optionally substituted heteroaryl and said R₁ is attached to the3- or 4-position of the phenyl ring; Each R₂ is hydrogen, an optionallysubstituted C₁₋₆ aliphatic, an optionally substituted C₃₋₆cycloaliphatic, an optionally substituted phenyl, or an optionallysubstituted heteroaryl; Ring A is an optionally substitutedcycloaliphatic or an optionally substituted heterocycloaliphatic wherethe atoms of ring A adjacent to C* are carbon atoms, and said ring A isoptionally substituted with 1, 2, or 3 substituents; Each R₄ is anoptionally substituted aryl or an optionally substituted heteroaryl; andEach n is 1, 2, 3, 4, or
 5. 71. The method of claim 70, wherein the ABCtransporter is CFTR.
 72. A method of treating or lessening the severityof a disease in a patient, wherein said disease is selected from cysticfibrosis, hereditary emphysema, hereditary hemochromatosis,coagulation-fibrinolysis deficiencies, such as protein C deficiency,Type 1 hereditary angioedema, lipid processing deficiencies, such asfamilial hypercholesterolemia, Type 1 chylomicronemia,abetalipoproteinemia, lysosomal storage diseases, such as I-celldisease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetesmellitus, Laron dwarfism, myleoperoxidase deficiency, primaryhypoparathyroidism, melanoma, glycanosis CDG type 1, congenitalhyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia,ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI,Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, progressive supranuclear plasy,Pick's disease, several polyglutamine neurological disorders asuch asHuntington, spinocerebullar ataxia type I, spinal and bulbar muscularatrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well asspongiform encephalopathies, such as hereditary Creutzfeldt-Jakobdisease (due to prion protein processing defect), Fabry disease,Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren'sdisease, said method comprising the step of administering to saidpatient an effective amount of a compound of formula I according toclaim
 1. 73. A kit for use in measuring the activity of an ABCtransporter or a fragment thereof in a biological sample in vitro or invivo, comprising: (i) a composition comprising a compound of formula (I)according to claim 1; and (ii) instructions for: a) contacting thecomposition with the biological sample; and b) measuring activity ofsaid ABC transporter or a fragment thereof.
 74. The kit of claim 73,further comprising instructions for a) contacting an additionalcomposition with the biological sample; b) measuring the activity ofsaid ABC transporter or a fragment thereof in the presence of saidadditional compound; and c) comparing the activity of the ABCtransporter in the presence of the additional compound with the densityof the ABC transporter in the presence of a composition of formula (I).75. The kit of claim 73 or claim 74, wherein the kit is used to measurethe density of CFTR.